Log in

Rho GTPases in cancer radiotherapy and metastasis

  • Non-Thematics Review
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Despite treatment advances, radioresistance and metastasis markedly impair the benefits of radiotherapy to patients with malignancies. Functioning as molecular switches, Rho guanosine triphosphatases (GTPases) have well-recognized roles in regulating various downstream signaling pathways in a wide range of cancers. In recent years, accumulating evidence indicates the involvement of Rho GTPases in cancer radiotherapeutic efficacy and metastasis, as well as radiation-induced metastasis. The functions of Rho GTPases in radiotherapeutic efficacy are divergent and context-dependent; thereby, a comprehensive integration of their roles and correlated mechanisms is urgently needed. This review integrates current evidence supporting the roles of Rho GTPases in mediating radiotherapeutic efficacy and the underlying mechanisms. In addition, their correlations with metastasis and radiation-induced metastasis are discussed. Under the prudent application of Rho GTPase inhibitors based on critical evaluations of biological contexts, targeting Rho GTPases can be a promising strategy in overcoming radioresistance and simultaneously reducing the metastatic potential of tumor cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Goitre, L., Trapani, E., Trabalzini, L., & Retta, S. F. (2014). The Ras superfamily of small GTPases: the unlocked secrets. In Ras signaling (pp. 1–18). Springer.

  2. Hodge, R. G., & Ridley, A. J. (2016). Regulating Rho GTPases and their regulators. Nature Reviews Molecular Cell Biology, 17(8), 496–510.

    CAS  PubMed  Google Scholar 

  3. Cardama, G., Gonzalez, N., Maggio, J., Menna, P. L., & Gomez, D. (2017). Rho GTPases as therapeutic targets in cancer. International Journal of Oncology, 51(4), 1025–1034.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ulu, A., & Frost, J. A. (2016). Regulation of RhoA activation and cytoskeletal organization by acetylation. Small GTPases, 7(2), 76–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Cherfils, J., & Zeghouf, M. (2013). Regulation of small gtpases by gefs, gaps, and gdis. Physiological Reviews, 93(1), 269–309.

    CAS  PubMed  Google Scholar 

  6. Tang, Z., Li, C., Kang, B., Gao, G., Li, C., & Zhang, Z. (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Research, 45(W1), W98–W102.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Woldu, S. L., Hutchinson, R. C., Krabbe, L.-M., Sanli, O., & Margulis, V. (2018). The Rho GTPase signalling pathway in urothelial carcinoma. Nature Reviews Urology, 15(2), 83–91.

    CAS  PubMed  Google Scholar 

  8. Cho, H. J., Kim, J.-T., Baek, K. E., Kim, B.-Y., & Lee, H. G. (2019). Regulation of Rho GTPases by RhoGDIs in human cancers. Cells, 8(9), 1037.

    CAS  PubMed Central  Google Scholar 

  9. Orgaz, J. L., Herraiz, C., & Sanz-Moreno, V. (2014). Rho GTPases modulate malignant transformation of tumor cells. Small GTPases, 5(4), e983867.

    Google Scholar 

  10. Bernier, J., Domenge, C., Ozsahin, M., Matuszewska, K., Lefèbvre, J.-L., Greiner, R. H., Giralt, J., Maingon, P., Rolland, F., Bolla, M., Cognetti, F., Bourhis, J., Kirkpatrick, A., van Glabbeke, M., & European Organization for Research and Treatment of Cancer Trial 22931. (2004). Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. New England Journal of Medicine, 350(19), 1945–1952.

    CAS  PubMed  Google Scholar 

  11. Lievens, Y., Gospodarowicz, M., Grover, S., Jaffray, D., Rodin, D., Torode, J., Yap, M. L., Zubizarreta, E., & GIRO Steering and Advisory Committees. (2017). Global impact of radiotherapy in oncology: saving one million lives by 2035. Radiotherapy and Oncology, 125(2), 175–177.

    PubMed  Google Scholar 

  12. Mihai, M., Spunei, M., & Malaescu, I. (2014). Comparison features for proton and heavy ion beams versus photon and electron beams. Romanian Reports in Physics, 66(1), 212–222.

    Google Scholar 

  13. Flejmer, A. M., Nyström, P. W., Dohlmar, F., Josefsson, D., & Dasu, A. (2015). Potential benefit of scanned proton beam versus photons as adjuvant radiation therapy in breast cancer. International Journal of Particle Therapy, 1(4), 845–855.

    Google Scholar 

  14. Hogstrom, K. R., & Almond, P. R. (2006). Review of electron beam therapy physics. Physics in Medicine & Biology, 51(13), R455–R489.

    CAS  Google Scholar 

  15. Salem, A., Mohamad, I., Dayyat, A., Kanaa’n, H., Sarhan, N., Roujob, I., Salem, A. F., Afifi, S., Jaradat, I., Mubiden, R., & Almousa, A. (2015). Combined photon-electron beams in the treatment of the supraclavicular lymph nodes in breast cancer: a novel technique that achieves adequate coverage while reducing lung dose. Medical Dosimetry, 40(3), 210–217.

    PubMed  Google Scholar 

  16. Schulz-Ertner, D., & Tsujii, H. (2007). Particle radiation therapy using proton and heavier ion beams. Journal of Clinical Oncology, 25(8), 953–964.

    PubMed  Google Scholar 

  17. Borrego-Soto, G., Ortiz-López, R., & Rojas-Martínez, A. (2015). Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer. Genetics and Molecular Biology, 38(4), 420–432.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mahaney, B. L., Meek, K., & Lees-Miller, S. P. (2009). Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochemical Journal, 417(3), 639–650.

    CAS  PubMed  Google Scholar 

  19. Valastyan, S., & Weinberg, R. A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147(2), 275–292.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Chiang, S. P., Cabrera, R. M., & Segall, J. E. (2016). Tumor cell intravasation. American Journal of Physiology-Cell Physiology, 311(1), C1–C14.

    PubMed  PubMed Central  Google Scholar 

  21. Izdebska, M., Zielińska, W., Grzanka, D., & Gagat, M. (2018). The role of actin dynamics and actin-binding proteins expression in epithelial-to-mesenchymal transition and its association with cancer progression and evaluation of possible therapeutic targets. BioMed Research International, 2018, 113.

    Google Scholar 

  22. Wang, W., Liu, Y., & Liao, K. (2011). Tyrosine phosphorylation of cortactin by the FAK-Src complex at focal adhesions regulates cell motility. BMC Cell Biology, 12(1), 49.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sit, S.-T., & Manser, E. (2011). Rho GTPases and their role in organizing the actin cytoskeleton. Journal of Cell Science, 124(5), 679–683.

    CAS  PubMed  Google Scholar 

  24. Stephens, S. J., Moravan, M. J., & Salama, J. K. (2018). Managing patients with oligometastatic non–small-cell lung cancer. Journal of Oncology Practice, 14(1), 23–31.

    PubMed  Google Scholar 

  25. Ordoñez, R., Otero, A., Jerez, I., Medina, J. A., Lupiañez-Pérez, Y., & Gomez-Millan, J. (2019). Role of radiotherapy in the treatment of metastatic head and neck cancer. Oncotargets and Therapy, 12, 677–683.

    PubMed  PubMed Central  Google Scholar 

  26. Lutz, S. T., Jones, J., & Chow, E. (2014). Role of radiation therapy in palliative care of the patient with cancer. Journal of Clinical Oncology, 32(26), 2913–2919.

    PubMed  PubMed Central  Google Scholar 

  27. Dillekås, H., Rogers, M. S., & Straume, O. (2019). Are 90% of deaths from cancer caused by metastases? Cancer Medicine, 8(12), 5574–5576.

    PubMed  PubMed Central  Google Scholar 

  28. Kim, M.-J., Byun, J.-Y., Yun, C.-H., Park, I.-C., Lee, K.-H., & Lee, S.-J. (2008). c-Src-p38 mitogen-activated protein kinase signaling is required for Akt activation in response to ionizing radiation. Molecular Cancer Research, 6(12), 1872–1880.

    CAS  PubMed  Google Scholar 

  29. Yan, Y., Greer, P. M., Cao, P. T., Kolb, R. H., & Cowan, K. H. (2012). RAC1 GTPase plays an important role in γ-irradiation induced G 2/M checkpoint activation. Breast Cancer Research, 14(2), R60.

    CAS  PubMed  Google Scholar 

  30. Yan, Y., Hein, A. L., Etekpo, A., Burchett, K. M., Lin, C., Enke, C. A., Batra, S. K., Cowan, K. H., & Ouellette, M. M. (2014). Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation. Oncotarget, 5(21), 10251–10270.

    PubMed  PubMed Central  Google Scholar 

  31. Skvortsov, S., Dudas, J., Eichberger, P., Witsch-Baumgartner, M., Loeffler-Ragg, J., Pritz, C., et al. (2014). Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC). British Journal of Cancer, 110(11), 2677–2687.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Espinha, G., Osaki, J. H., Magalhaes, Y. T., & Forti, F. L. (2015). Rac1 GTPase-deficient HeLa cells present reduced DNA repair, proliferation, and survival under UV or gamma irradiation. Molecular and Cellular Biochemistry, 404(1–2), 281–297.

    CAS  PubMed  Google Scholar 

  33. Hein, A. L., Post, C. M., Sheinin, Y. M., Lakshmanan, I., Natarajan, A., Enke, C. A., Batra, S. K., Ouellette, M. M., & Yan, Y. (2016). RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment. Oncogene, 35(49), 6319–6329.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhou, T., Wang, C. H., Yan, H., Zhang, R., Zhao, J. B., Qian, C. F., et al. (2016). Inhibition of the Rac1-WAVE2-Arp2/3 signaling pathway promotes radiosensitivity via downregulation of cofilin-1 in U251 human glioma cells. Molecular Medicine Reports, 13(5), 4414–4420.

    CAS  PubMed  Google Scholar 

  35. Zhou, Y., Liao, Q., Han, Y., Chen, J., Liu, Z., Ling, H., Zhang, J., Yang, W., Oyang, L., **a, L., Wang, L., Wang, H., Xue, L., Wang, H., & Hu, B. (2016). Rac1 overexpression is correlated with epithelial mesenchymal transition and predicts poor prognosis in non-small cell lung cancer. Journal of Cancer, 7(14), 2100–2109.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Choi, S.-Y., Kim, M.-J., Kang, C.-M., Bae, S., Cho, C.-K., Soh, J.-W., Kim, J. H., Kang, S., Chung, H. Y., Lee, Y. S., & Lee, S. J. (2006). Activation of Bak and Bax through c-abl-protein kinase Cδ-p38 MAPK signaling in response to ionizing radiation in human non-small cell lung cancer cells. Journal of Biological Chemistry, 281(11), 7049–7059.

    CAS  PubMed  Google Scholar 

  37. Duan, W., Xu, Y., Dong, Y., Cao, L., Tong, J., & Zhou, X. (2013). Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway. Journal of Radiation Research, 54(4), 611–619.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang, C., Pan, Z., Hou, H., Li, D., Mo, Y., Mo, C., & Li, J. (2016). The enhancement of radiation sensitivity in nasopharyngeal carcinoma cells via activation of the Rac1/NADPH signaling pathway. Radiation Research, 185(6), 638–646.

    CAS  PubMed  Google Scholar 

  39. Su, Z., Li, Z., Wang, C., Tian, W., Lan, F., Liang, D., Li, J., Li, D., & Hou, H. (2019). A novel Rhein derivative: activation of Rac1/NADPH pathway enhances sensitivity of nasopharyngeal carcinoma cells to radiotherapy. Cellular Signalling, 54, 35–45.

    CAS  PubMed  Google Scholar 

  40. Zhao, M., Chen, L., **ao, Y., **ao, H., & Liu, H. (2019). Impact on U251 glioma cell radiosensitivity and CFL1 level via inhibiting cell motility regulator ROCKII of RhoA-RockII-CFL1 pathway. American Society of Clinical Oncology, 37:15_suppl, e14630–e14630.

  41. McLaughlin, N., Annabi, B., Bouzeghrane, M., Temme, A., Bahary, J.-P., Moumdjian, R., & Béliveau, R. (2006). The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (−)-epigallocatechin-3-gallate. Brain Research, 1071(1), 1–9.

    CAS  PubMed  Google Scholar 

  42. Ader, I., Toulas, C., Dalenc, F., Delmas, C., Bonnet, J., Cohen-Jonathan, E., & Favre, G. (2002). RhoB controls the 24 kDa FGF-2-induced radioresistance in HeLa cells by preventing post-mitotic cell death. Oncogene, 21(39), 5998–6006.

    CAS  PubMed  Google Scholar 

  43. Ader, I., Delmas, C., Bonnet, J., Rochaix, P., Favre, G., Toulas, C., & Cohen-Jonathan-Moyal, E. (2003). Inhibition of Rho pathways induces radiosensitization and oxygenation in human glioblastoma xenografts. Oncogene, 22(55), 8861–8869.

    CAS  PubMed  Google Scholar 

  44. Delmas, C., Heliez, C., Cohen-Jonathan, E., End, D., Bonnet, J., Favre, G., & Toulas, C. (2002). Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation. International Journal of Cancer, 100(1), 43–48.

    CAS  PubMed  Google Scholar 

  45. Monferran, S., Skuli, N., Delmas, C., Favre, G., Bonnet, J., Cohen-Jonathan-Moyal, E., & Toulas, C. (2008). Alphavbeta3 and alphavbeta5 integrins control glioma cell response to ionising radiation through ILK and RhoB. International Journal of Cancer, 123(2), 357–364. https://doi.org/10.1002/ijc.23498.

    Article  CAS  PubMed  Google Scholar 

  46. Liu, N., Cui, W., Jiang, X., Zhang, Z., Gnosa, S., Ali, Z., et al. (2019). The critical role of dysregulated RhoB signaling pathway in radioresistance of colorectal cancer. International Journal of Radiation Oncology* Biology* Physics, 104(5), 1153–1164..

  47. Luis-Ravelo, D., Antón, I., Zandueta, C., Valencia, K., Pajares, M.-J., Agorreta, J., Montuenga, L., Vicent, S., Wistuba, I. I., de Las Rivas, J., & Lecanda, F. (2014). RHOB influences lung adenocarcinoma metastasis and resistance in a host-sensitive manner. Molecular Oncology, 8(2), 196–206.

    CAS  PubMed  Google Scholar 

  48. Liu, A.-x., Cerniglia, G. J., Bernhard, E. J., & Prendergast, G. C. (2001). RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage. Proceedings of the National Academy of Sciences, 98(11), 6192–6197.

    Google Scholar 

  49. Kim, C.-H., Won, M., Choi, C.-H., Ahn, J., Kim, B.-K., Song, K.-B., Kang, C. M., & Chung, K. S. (2010). Increase of RhoB in γ-radiation-induced apoptosis is regulated by c-Jun N-terminal kinase in Jurkat T cells. Biochemical and Biophysical Research Communications, 391(2), 1182–1186.

    CAS  PubMed  Google Scholar 

  50. Skvortsov, S., Debbage, P., Cho, W. C., Lukas, P., & Skvortsova, I. (2014). Putative biomarkers and therapeutic targets associated with radiation resistance. Expert Review of Proteomics, 11(2), 207–214.

    CAS  PubMed  Google Scholar 

  51. Skvortsov, S., Jimenez, C. R., Knol, J. C., Eichberger, P., Schiestl, B., Debbage, P., Skvortsova, I., & Lukas, P. (2011). Radioresistant head and neck squamous cell carcinoma cells: intracellular signaling, putative biomarkers for tumor recurrences and possible therapeutic targets. Radiotherapy and Oncology, 101(1), 177–182.

    CAS  PubMed  Google Scholar 

  52. Osaki, J. H., Espinha, G., Magalhaes, Y. T., & Forti, F. L. (2016). Modulation of RhoA GTPase activity sensitizes human cervix carcinoma cells to γ-radiation by attenuating DNA repair pathways. Oxidative Medicine and Cellular Longevity, 2016, 111.

    Google Scholar 

  53. Ju, J., & Gilkes, D. (2018). RhoB: team oncogene or team tumor suppressor? Genes, 9(2), 67.

    PubMed Central  Google Scholar 

  54. Toulany, M. (2019). Targeting DNA double-strand break repair pathways to improve radiotherapy response. Genes (Basel), 10(1). https://doi.org/10.3390/genes10010025.

  55. Lee, J., & Paull, T. T. (2007). Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene, 26(56), 7741–7748.

    CAS  PubMed  Google Scholar 

  56. Marampon, F., Ciccarelli, C., & Zani, B. M. (2019). Biological rationale for targeting MEK/ERK pathways in anti-cancer therapy and to potentiate tumour responses to radiation. International Journal of Molecular Sciences, 20(10), 2530. https://doi.org/10.3390/ijms20102530.

    Article  CAS  PubMed Central  Google Scholar 

  57. Bai, M., Ma, X., Li, X., Wang, X., Mei, Q., Li, X., Wu, Z., & Han, W. (2015). The accomplices of NF-κB lead to radioresistance. Current Protein & Peptide Science, 16(4), 279–294. https://doi.org/10.2174/138920371604150429152328.

    Article  CAS  Google Scholar 

  58. Yan, H., Yang, K., **ao, H., Zou, Y. J., Zhang, W. B., & Liu, H. Y. (2012). Over-expression of cofilin-1 and phosphoglycerate kinase 1 in astrocytomas involved in pathogenesis of radioresistance. CNS Neuroscience & Therapeutics, 18(9), 729–736.

    CAS  Google Scholar 

  59. Leu, J.-D., Chiu, Y.-W., Lo, C.-C., Chiang, P.-H., Chiu, S.-J., Tsai, C.-H., Hwang, J. J., Chen, R. C., Gorbunova, V., & Lee, Y. J. (2013). Enhanced cellular radiosensitivity induced by cofilin-1 over-expression is associated with reduced DNA repair capacity. International Journal of Radiation Biology, 89(6), 433–444.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ishikawa, K., Ishii, H., & Saito, T. (2006). DNA damage-dependent cell cycle checkpoints and genomic stability. DNA and Cell Biology, 25(7), 406–411.

    CAS  PubMed  Google Scholar 

  61. Lu, Q., Insinna, C., Ott, C., Stauffer, J., Pintado, P. A., Rahajeng, J., Baxa, U., Walia, V., Cuenca, A., Hwang, Y. S., Daar, I. O., Lopes, S., Lippincott-Schwartz, J., Jackson, P. K., Caplan, S., & Westlake, C. J. (2015). Early steps in primary cilium assembly require EHD1/EHD3-dependent ciliary vesicle formation. Nature Cell Biology, 17(3), 228–240.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Van Laethem, A., Van Kelst, S., Lippens, S., Declercq, W., Vandenabeele, P., Janssens, S., et al. (2004). Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 18(15), 1946–1948. https://doi.org/10.1096/fj.04-2285fje.

    Article  CAS  Google Scholar 

  63. Oh, W., & Frost, J. A. (2014). Rho gtpase independent regulation of atm activation and cell survival by the rhogef net1a. Cell Cycle, 13(17), 2765–2772.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Skuli, N., Monferran, S., Delmas, C., Lajoie-Mazenc, I., Favre, G., Toulas, C., & Cohen-Jonathan-Moyal, E. (2006). Activation of RhoB by hypoxia controls hypoxia-inducible factor-1α stabilization through glycogen synthase kinase-3 in U87 glioblastoma cells. Cancer Research, 66(1), 482–489.

    CAS  PubMed  Google Scholar 

  65. **a, Y., Jiang, L., & Zhong, T. (2018). The role of HIF-1α in chemo-/radioresistant tumors. Oncotargets and Therapy, 11, 3003–3011.

    PubMed  PubMed Central  Google Scholar 

  66. Pei, H., Zhang, J., Nie, J., Ding, N., Hu, W., Hua, J., Hirayama, R., Furusawa, Y., Liu, C., Li, B., Hei, T. K., & Zhou, G. (2017). RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation. Cell Cycle, 16(1), 113–122.

    CAS  PubMed  Google Scholar 

  67. Pranatharthi, A., Thomas, P., Udayashankar, A. H., Bhavani, C., Suresh, S. B., Krishna, S., et al. (2019). RhoC regulates radioresistance via crosstalk of ROCK2 with the DNA repair machinery in cervical cancer. Journal of Experimental & Clinical Cancer Research, 38(1), 1–24.

    CAS  Google Scholar 

  68. Moharil, R. B., Dive, A., Khandekar, S., & Bodhade, A. (2017). Cancer stem cells: an insight. Journal of Oral and Maxillofacial Pathology, 21(3), 463. https://doi.org/10.4103/jomfp.JOMFP_132_16.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Maugeri-Saccà, M., Bartucci, M., & De Maria, R. (2012). DNA damage repair pathways in cancer stem cells. Molecular Cancer Therapeutics, 11(8), 1627–1636. https://doi.org/10.1158/1535-7163.Mct-11-1040.

    Article  PubMed  Google Scholar 

  70. Ding, S., Li, C., Cheng, N., Cui, X., Xu, X., & Zhou, G. (2015). Redox regulation in cancer stem cells. Oxidative Medicine and Cellular Longevity, 2015, 750798–750711. https://doi.org/10.1155/2015/750798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Chen, W., Dong, J., Haiech, J., Kilhoffer, M. C., & Zeniou, M. (2016). Cancer stem cell quiescence and plasticity as major challenges in cancer therapy. Stem Cells International, 2016, 1740936–1740916. https://doi.org/10.1155/2016/1740936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schulz, A., Meyer, F., Dubrovska, A., & Borgmann, K. (2019). Cancer stem cells and radioresistance: DNA repair and beyond. Cancers (Basel), 11(6). https://doi.org/10.3390/cancers11060862.

  73. Krause, M., Dubrovska, A., Linge, A., & Baumann, M. (2017). Cancer stem cells: radioresistance, prediction of radiotherapy outcome and specific targets for combined treatments. Advanced Drug Delivery Reviews, 109, 63–73. https://doi.org/10.1016/j.addr.2016.02.002.

    Article  CAS  PubMed  Google Scholar 

  74. Jiang, Z. B., Ma, B. Q., Liu, S. G., Li, J., Yang, G. M., Hou, Y. B., Si, R. H., Gao, P., & Yan, H. T. (2019). miR-365 regulates liver cancer stem cells via RAC1 pathway. Molecular Carcinogenesis, 58(1), 55–65. https://doi.org/10.1002/mc.22906.

    Article  CAS  PubMed  Google Scholar 

  75. Chen, S., Li, H., Li, S., Yu, J., Wang, M., **ng, H., Tang, K., Tian, Z., Rao, Q., & Wang, J. (2016). Rac1 GTPase promotes interaction of hematopoietic stem/progenitor cell with niche and participates in leukemia initiation and maintenance in mouse. Stem Cells, 34(7), 1730–1741. https://doi.org/10.1002/stem.2348.

    Article  CAS  PubMed  Google Scholar 

  76. Yoon, C., Cho, S. J., Chang, K. K., Park, D. J., Ryeom, S. W., & Yoon, S. S. (2017). Role of Rac1 pathway in epithelial-to-mesenchymal transition and cancer stem-like cell phenotypes in gastric adenocarcinoma. Molecular Cancer Research, 15(8), 1106–1116. https://doi.org/10.1158/1541-7786.Mcr-17-0053.

    Article  CAS  PubMed  Google Scholar 

  77. Yoon, C. H., Hyun, K. H., Kim, R. K., Lee, H., Lim, E. J., Chung, H. Y., An, S., Park, M. J., Suh, Y., Kim, M. J., & Lee, S. J. (2011). The small GTPase Rac1 is involved in the maintenance of stemness and malignancies in glioma stem-like cells. FEBS Letters, 585(14), 2331–2338. https://doi.org/10.1016/j.febslet.2011.05.070.

    Article  CAS  PubMed  Google Scholar 

  78. Yoon, C., Cho, S. J., Aksoy, B. A., Park, D. J., Schultz, N., Ryeom, S. W., & Yoon, S. S. (2016). Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells. Clinical Cancer Research, 22(4), 971–983. https://doi.org/10.1158/1078-0432.Ccr-15-1356.

    Article  CAS  PubMed  Google Scholar 

  79. Nandy, S. B., Orozco, A., Lopez-Valdez, R., Roberts, R., Subramani, R., Arumugam, A., Dwivedi, A. K., Stewart, V., Prabhakar, G., Jones, S., & Lakshmanaswamy, R. (2017). Glucose insult elicits hyperactivation of cancer stem cells through miR-424-cdc42-prdm14 signalling axis. British Journal of Cancer, 117(11), 1665–1675. https://doi.org/10.1038/bjc.2017.335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dong, Z., Yu, C., Rezhiya, K., Gulijiahan, A., & Wang, X. (2019). Downregulation of miR-146a promotes tumorigenesis of cervical cancer stem cells via VEGF/CDC42/PAK1 signaling pathway. Artificial Cells, Nanomedicine, and Biotechnology, 47(1), 3711–3719. https://doi.org/10.1080/21691401.2019.1664560.

    Article  CAS  PubMed  Google Scholar 

  81. Binker, M. G., Binker-Cosen, A. A., Richards, D., Oliver, B., & Cosen-Binker, L. I. (2009). EGF promotes invasion by PANC-1 cells through Rac1/ROS-dependent secretion and activation of MMP-2. Biochemical and Biophysical Research Communications, 379(2), 445–450. https://doi.org/10.1016/j.bbrc.2008.12.080.

    Article  CAS  PubMed  Google Scholar 

  82. Kang, M. A., So, E. Y., Simons, A. L., Spitz, D. R., & Ouchi, T. (2012). DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway. Cell Death & Disease, 3(1), e249. https://doi.org/10.1038/cddis.2011.134.

    Article  CAS  Google Scholar 

  83. Diebold, B. A., Fowler, B., Lu, J., Dinauer, M. C., & Bokoch, G. M. (2004). Antagonistic cross-talk between Rac and Cdc42 GTPases regulates generation of reactive oxygen species. The Journal of Biological Chemistry, 279(27), 28136–28142. https://doi.org/10.1074/jbc.M313891200.

    Article  CAS  PubMed  Google Scholar 

  84. Aghajanian, A., Wittchen, E. S., Campbell, S. L., & Burridge, K. (2009). Direct activation of RhoA by reactive oxygen species requires a redox-sensitive motif. PLoS One, 4(11), e8045. https://doi.org/10.1371/journal.pone.0008045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhu, W., Ma, L., Yang, B., Zheng, Z., Chai, R., Liu, T., Liu, Z., Song, T., Li, F., & Li, G. (2016). Flavone inhibits migration through DLC1/RhoA pathway by decreasing ROS generation in breast cancer cells. In Vitro Cellular & Developmental Biology. Animal, 52(5), 589–597. https://doi.org/10.1007/s11626-016-0010-8.

    Article  CAS  Google Scholar 

  86. MacKay, C. E., Shaifta, Y., Snetkov, V. V., Francois, A. A., Ward, J. P. T., & Knock, G. A. (2017). ROS-dependent activation of RhoA/Rho-kinase in pulmonary artery: role of Src-family kinases and ARHGEF1. Free Radical Biology & Medicine, 110, 316–331. https://doi.org/10.1016/j.freeradbiomed.2017.06.022.

    Article  CAS  Google Scholar 

  87. Chung, K. S., Han, G., Kim, B. K., Kim, H. M., Yang, J. S., Ahn, J., Lee, K., Song, K. B., & Won, M. (2013). A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROS-mediated c-Abl/p38 MAPK signaling. Cancer Chemotherapy and Pharmacology, 72(6), 1315–1324. https://doi.org/10.1007/s00280-013-2310-y.

    Article  CAS  PubMed  Google Scholar 

  88. Pan, J., She, M., Xu, Z. X., Sun, L., & Yeung, S. C. (2005). Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells. Cancer Research, 65(9), 3671–3681. https://doi.org/10.1158/0008-5472.Can-04-2744.

    Article  CAS  PubMed  Google Scholar 

  89. Wu, W., & Zhao, S. (2013). Metabolic changes in cancer: beyond the Warburg effect. Acta Biochimica et Biophysica Sinica, 45(1), 18–26. https://doi.org/10.1093/abbs/gms104.

    Article  CAS  PubMed  Google Scholar 

  90. Sharma, A., Boise, L. H., & Shanmugam, M. (2019). Cancer metabolism and the evasion of apoptotic cell death. Cancers (Basel), 11(8). https://doi.org/10.3390/cancers11081144.

  91. Shimura, T., Noma, N., Sano, Y., Ochiai, Y., Oikawa, T., Fukumoto, M., & Kunugita, N. (2014). AKT-mediated enhanced aerobic glycolysis causes acquired radioresistance by human tumor cells. Radiotherapy and Oncology, 112(2), 302–307. https://doi.org/10.1016/j.radonc.2014.07.015.

    Article  CAS  PubMed  Google Scholar 

  92. Meng, M. B., Wang, H. H., Guo, W. H., Wu, Z. Q., Zeng, X. L., Zaorsky, N. G., et al. (2015). Targeting pyruvate kinase M2 contributes to radiosensitivity of non-small cell lung cancer cells in vitro and in vivo. Cancer Letters, 356(2 Pt B), 985–993. https://doi.org/10.1016/j.canlet.2014.11.016.

    Article  CAS  PubMed  Google Scholar 

  93. Zhong, J. T., & Zhou, S. H. (2017). Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma. Oncotarget, 8(8), 14133–14146. https://doi.org/10.18632/oncotarget.13044.

    Article  PubMed  Google Scholar 

  94. Isebaert, S. F., Swinnen, J. V., McBride, W. H., Begg, A. C., & Haustermans, K. M. (2011). 5-aminoimidazole-4-carboxamide riboside enhances effect of ionizing radiation in PC3 prostate cancer cells. International Journal of Radiation Oncology, Biology, Physics, 81(5), 1515–1523. https://doi.org/10.1016/j.ijrobp.2011.06.1964.

    Article  CAS  PubMed  Google Scholar 

  95. Efimova, E. V., Takahashi, S., Shamsi, N. A., Wu, D., Labay, E., Ulanovskaya, O. A., Weichselbaum, R. R., Kozmin, S. A., & Kron, S. J. (2016). Linking cancer metabolism to DNA repair and accelerated senescence. Molecular Cancer Research, 14(2), 173–184. https://doi.org/10.1158/1541-7786.Mcr-15-0263.

    Article  CAS  PubMed  Google Scholar 

  96. Lee, M., & Yoon, J. H. (2015). Metabolic interplay between glycolysis and mitochondrial oxidation: the reverse Warburg effect and its therapeutic implication. World Journal of Biological Chemistry, 6(3), 148–161. https://doi.org/10.4331/wjbc.v6.i3.148.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S. W., & Kreutz, M. (2007). Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood, 109(9), 3812–3819. https://doi.org/10.1182/blood-2006-07-035972.

    Article  CAS  PubMed  Google Scholar 

  98. Zeng, R. J., Zheng, C. W., Gu, J. E., Zhang, H. X., **e, L., Xu, L. Y., & Li, E. M. (2019). RAC1 inhibition reverses cisplatin resistance in esophageal squamous cell carcinoma and induces downregulation of glycolytic enzymes. Molecular Oncology, 13(9), 2010–2030. https://doi.org/10.1002/1878-0261.12548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang, Y., Du, J., Hu, Z., Liu, J., Tian, Y., Zhu, Y., et al. (2011). Activation of Rac1-PI3K/Akt is required for epidermal growth factor-induced PAK1 activation and cell migration in MDA-MB-231 breast cancer cells. Journal of Biomedical Research, 25(4), 237–245. https://doi.org/10.1016/s1674-8301(11)60032-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang, C., Liu, J., Liang, Y., Wu, R., Zhao, Y., Hong, X., Lin, M., Yu, H., Liu, L., Levine, A. J., Hu, W., & Feng, Z. (2013). Tumour-associated mutant p53 drives the Warburg effect. Nature Communications, 4, 2935. https://doi.org/10.1038/ncomms3935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Baxter, E., Windloch, K., Gannon, F., & Lee, J. S. (2014). Epigenetic regulation in cancer progression. Cell & Bioscience, 4, 45. https://doi.org/10.1186/2045-3701-4-45.

    Article  CAS  Google Scholar 

  102. Chen, Q. W., Zhu, X. Y., Li, Y. Y., & Meng, Z. Q. (2014). Epigenetic regulation and cancer (review). Oncology Reports, 31(2), 523–532. https://doi.org/10.3892/or.2013.2913.

    Article  CAS  PubMed  Google Scholar 

  103. Wan, J., Su, Y., Song, Q., Tung, B., Oyinlade, O., Liu, S., et al. (2017). Methylated cis-regulatory elements mediate KLF4-dependent gene transactivation and cell migration. Elife, 6. https://doi.org/10.7554/eLife.20068.

  104. Dopeso, H., Rodrigues, P., Bilic, J., Bazzocco, S., Cartón-García, F., Macaya, I., de Marcondes, P. G., Anguita, E., Masanas, M., Jiménez-Flores, L. M., Martínez-Barriocanal, Á., Nieto, R., Segura, M. F., Schwartz Jr, S., Mariadason, J. M., & Arango, D. (2018). Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer. British Journal of Cancer, 118(1), 106–116. https://doi.org/10.1038/bjc.2017.420.

    Article  CAS  PubMed  Google Scholar 

  105. Mazières, J., Tovar, D., He, B., Nieto-Acosta, J., Marty-Detraves, C., Clanet, C., Pradines, A., Jablons, D., & Favre, G. (2007). Epigenetic regulation of RhoB loss of expression in lung cancer. BMC Cancer, 7, 220. https://doi.org/10.1186/1471-2407-7-220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gómez Del Pulgar, T., Valdés-Mora, F., Bandrés, E., Pérez-Palacios, R., Espina, C., Cejas, P., et al. (2008). Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism. International Journal of Oncology, 33(1), 185–193.

    PubMed  Google Scholar 

  107. Barrio-Real, L., Benedetti, L. G., Engel, N., Tu, Y., Cho, S., Sukumar, S., & Kazanietz, M. G. (2014). Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation. Breast Cancer Research, 16(5), 441. https://doi.org/10.1186/s13058-014-0441-7.

    Article  CAS  PubMed  Google Scholar 

  108. Kasuya, K., Nagakawa, Y., Hosokawa, Y., Sahara, Y., Takishita, C., Nakajima, T., et al. (2016). RhoA activity increases due to hypermethylation of ARHGAP28 in a highly liver-metastatic colon cancer cell line. Biomedical Reports, 4(3), 335–339. https://doi.org/10.3892/br.2016.582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Delarue, F. L., Adnane, J., Joshi, B., Blaskovich, M. A., Wang, D. A., Hawker, J., Bizouarn, F., Ohkanda, J., Zhu, K., Hamilton, A. D., Chellappan, S., & Sebti, S. M. (2007). Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Oncogene, 26(5), 633–640. https://doi.org/10.1038/sj.onc.1209819.

    Article  CAS  PubMed  Google Scholar 

  110. Wahid, F., Shehzad, A., Khan, T., & Kim, Y. Y. (2010). MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochimica et Biophysica Acta, 1803(11), 1231–1243. https://doi.org/10.1016/j.bbamcr.2010.06.013.

    Article  CAS  PubMed  Google Scholar 

  111. Wang, P., Chen, L., Zhang, J., Chen, H., Fan, J., Wang, K., Luo, J., Chen, Z., Meng, Z., & Liu, L. (2014). Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1. Oncogene, 33(4), 514–524. https://doi.org/10.1038/onc.2012.598.

    Article  CAS  PubMed  Google Scholar 

  112. Ge, F., Wang, C., Wang, W., Liu, W., & Wu, B. (2017). MicroRNA-31 inhibits tumor invasion and metastasis by targeting RhoA in human gastric cancer. Oncology Reports, 38(2), 1133–1139. https://doi.org/10.3892/or.2017.5758.

    Article  CAS  PubMed  Google Scholar 

  113. Niu, S., Ma, X., Zhang, Y., Liu, Y. N., Chen, X., Gong, H., Yao, Y., Liu, K., & Zhang, X. (2018). MicroRNA-19a and microRNA-19b promote the malignancy of clear cell renal cell carcinoma through targeting the tumor suppressor RhoB. PLoS One, 13(2), e0192790. https://doi.org/10.1371/journal.pone.0192790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ke, T. W., Hsu, H. L., Wu, Y. H., Chen, W. T., Cheng, Y. W., & Cheng, C. W. (2014). MicroRNA-224 suppresses colorectal cancer cell migration by targeting Cdc42. Disease Markers, 2014, 617150–617111. https://doi.org/10.1155/2014/617150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mishima, T., Naotsuka, M., Horita, Y., Sato, M., Ohashi, K., & Mizuno, K. (2010). LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices. Biochemical and Biophysical Research Communications, 392(4), 577–581.

    CAS  PubMed  Google Scholar 

  116. Yamazaki, D., Kurisu, S., & Takenawa, T. (2009). Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. Oncogene, 28(13), 1570–1583.

    CAS  PubMed  Google Scholar 

  117. Zhang, Y., & Weinberg, R. A. (2018). Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Frontiers of Medicine, 12(4), 361–373.

    PubMed  PubMed Central  Google Scholar 

  118. Algayadh, I. G., Dronamraju, V., & Sylvester, P. W. (2016). Role of Rac1/WAVE2 signaling in mediating the inhibitory effects of γ-tocotrienol on mammary cancer cell migration and invasion. Biological and Pharmaceutical Bulletin, 39(12), 1974–1982.

    CAS  PubMed  Google Scholar 

  119. Deng, Q., Tian, Y.-X., & Liang, J. (2018). Mangiferin inhibits cell migration and invasion through Rac1/WAVE2 signalling in breast cancer. Cytotechnology, 70(2), 593–601.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Takenawa, T., & Miki, H. (2001). WASP and WAVE family proteins: key molecules for rapid rearrangement of cortical actin filaments and cell movement. Journal of Cell Science, 114(10), 1801–1809.

    CAS  PubMed  Google Scholar 

  121. Liu, C., Zhang, L., Cui, W., Du, J., Li, Z., Pang, Y., et al. (2019). Epigenetically upregulated GEFT-derived invasion and metastasis of rhabdomyosarcoma via epithelial mesenchymal transition promoted by the Rac1/Cdc42-PAK signalling pathway. EBioMedicine, 50, 122–134.

    PubMed  PubMed Central  Google Scholar 

  122. Fan, G. (2018). FER mediated HGF-independent regulation of HGFR/MET activates RAC1-PAK1 pathway to potentiate metastasis in ovarian cancer. Small GTPases, 11(3), 155–159.

  123. Fang, D., Chen, H., Zhu, J. Y., Wang, W., Teng, Y., Ding, H.-F., **g, Q., Su, S. B., & Huang, S. (2017). Epithelial–mesenchymal transition of ovarian cancer cells is sustained by Rac1 through simultaneous activation of MEK1/2 and Src signaling pathways. Oncogene, 36(11), 1546–1558.

    CAS  PubMed  Google Scholar 

  124. Zhang, C., Guo, F., Xu, G., Ma, J., & Shao, F. (2015). STAT3 cooperates with Twist to mediate epithelial-mesenchymal transition in human hepatocellular carcinoma cells. Oncology Reports, 33(4), 1872–1882.

    CAS  PubMed  Google Scholar 

  125. Zhou, K., Rao, J., Zhou, Z.-H., Yao, X.-H., Wu, F., Yang, J., et al. (2018). RAC1-GTP promotes epithelial-mesenchymal transition and invasion of colorectal cancer by activation of STAT3. Laboratory Investigation, 98(8), 989–998.

    CAS  PubMed  Google Scholar 

  126. Jiang, K., Lu, Q., Li, Q., Ji, Y., Chen, W., & Xue, X. (2017). Astragaloside IV inhibits breast cancer cell invasion by suppressing Vav3 mediated Rac1/MAPK signaling. International Immunopharmacology, 42, 195–202.

    CAS  PubMed  Google Scholar 

  127. Liu, Y., Cheng, Z., Pan, F., & Yan, W. (2017). MicroRNA-373 promotes growth and cellular invasion in osteosarcoma cells by activation of the PI3K/AKT-Rac1-JNK pathway: the potential role in spinal osteosarcoma. Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, 25(6), 989–999.

    CAS  Google Scholar 

  128. Sipes, N. S., Feng, Y., Guo, F., Lee, H.-O., Chou, F.-S., Cheng, J., Mulloy, J., & Zheng, Y. (2011). Cdc42 regulates extracellular matrix remodeling in three dimensions. Journal of Biological Chemistry, 286(42), 36469–36477.

    CAS  PubMed  Google Scholar 

  129. Gadea, G., Sanz-Moreno, V., Self, A., Godi, A., & Marshall, C. J. (2008). DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells. Current Biology, 18(19), 1456–1465.

    CAS  PubMed  Google Scholar 

  130. Wilkinson, S., Paterson, H. F., & Marshall, C. J. (2005). Cdc42–MRCK and Rho–ROCK signalling cooperate in myosin phosphorylation and cell invasion. Nature Cell Biology, 7(3), 255–261.

    CAS  PubMed  Google Scholar 

  131. Matsuoka, T., & Yashiro, M. (2014). Rho/ROCK signaling in motility and metastasis of gastric cancer. World journal of gastroenterology: WJG, 20(38), 13756–13766.

    CAS  PubMed  Google Scholar 

  132. Wei, L., Surma, M., Shi, S., Lambert-Cheatham, N., & Shi, J. (2016). Novel insights into the roles of Rho kinase in cancer. Archivum Immunologiae et Therapiae Experimentalis, 64(4), 259–278.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Campbell, H., Fleming, N., Roth, I., Mehta, S., Wiles, A., Williams, G., et al. (2018). ∆ 133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling. Nature Communications, 9(1), 254.

    PubMed  PubMed Central  Google Scholar 

  134. Amano, M., Nakayama, M., & Kaibuchi, K. (2010). Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton, 67(9), 545–554.

    CAS  PubMed  Google Scholar 

  135. Hwang, S. Y., Jung, J. W., Jeong, J. S., Kim, Y. J., Oh, E. S., Kim, T. H., Kim, J. Y., Cho, K. H., & Han, I. O. (2006). Dominant-negative Rac increases both inherent and ionizing radiation-induced cell migration in C6 rat glioma cells. International Journal of Cancer, 118(8), 2056–2063.

    CAS  PubMed  Google Scholar 

  136. Hamalukic, M., Huelsenbeck, J., Schad, A., Wirtz, S., Kaina, B., & Fritz, G. (2011). Rac1-regulated endothelial radiation response stimulates extravasation and metastasis that can be blocked by HMG-CoA reductase inhibitors. PLoS One, 6(10), e26413.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Murata, K., Noda, S.-E., Oike, T., Takahashi, A., Yoshida, Y., Suzuki, Y., et al. (2014). Increase in cell motility by carbon ion irradiation via the Rho signaling pathway and its inhibition by the ROCK inhibitor Y-27632 in lung adenocarcinoma A549 cells. Journal of Radiation Research, 55(4), 658–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhai, G. G., Malhotra, R., Delaney, M., Latham, D., Nestler, U., Zhang, M., Mukherjee, N., Song, Q., Robe, P., & Chakravarti, A. (2006). Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway. Journal of Neuro-Oncology, 76(3), 227–237.

    CAS  PubMed  Google Scholar 

  139. Fujita, M., Imadome, K., Endo, S., Shoji, Y., Yamada, S., & Imai, T. (2014). Nitric oxide increases the invasion of pancreatic cancer cells via activation of the PI3K–AKT and RhoA pathways after carbon ion irradiation. FEBS Letters, 588(17), 3240–3250.

    CAS  PubMed  Google Scholar 

  140. Fujita, M., Otsuka, Y., Imadome, K., Endo, S., Yamada, S., & Imai, T. (2012). Carbon-ion radiation enhances migration ability and invasiveness of the pancreatic cancer cell, PANC-1, in vitro. Cancer Science, 103(4), 677–683.

    CAS  PubMed  Google Scholar 

  141. Teng, Y., **e, X., Walker, S., White, D. T., Mumm, J. S., & Cowell, J. K. (2013). Evaluating human cancer cell metastasis in zebrafish. BMC Cancer, 13(1), 453.

    PubMed  PubMed Central  Google Scholar 

  142. Zheng, C.-W., Zeng, R.-J., Xu, L.-Y., & Li, E.-M. (2020). Rho GTPases: promising candidates for overcoming chemotherapeutic resistance. Cancer Letters, 475, 65–78.

    CAS  PubMed  Google Scholar 

  143. Duquette, P. M., & Lamarche-Vane, N. (2014). Rho GTPases in embryonic development. Small GTPases, 5(2), 8. https://doi.org/10.4161/sgtp.29716.

    Article  PubMed  Google Scholar 

  144. Sugihara, K., Nakatsuji, N., Nakamura, K., Nakao, K., Hashimoto, R., Otani, H., Sakagami, H., Kondo, H., Nozawa, S., Aiba, A., & Katsuki, M. (1998). Rac1 is required for the formation of three germ layers during gastrulation. Oncogene, 17(26), 3427–3433. https://doi.org/10.1038/sj.onc.1202595.

    Article  CAS  PubMed  Google Scholar 

  145. Takenaka, N., Nihata, Y., Ueda, S., & Satoh, T. (2017). In situ detection of the activation of Rac1 and RalA small GTPases in mouse adipocytes by immunofluorescent microscopy following in vivo and ex vivo insulin stimulation. Cellular Signalling, 39, 108–117. https://doi.org/10.1016/j.cellsig.2017.08.004.

    Article  CAS  PubMed  Google Scholar 

  146. Asahara, S., Shibutani, Y., Teruyama, K., Inoue, H. Y., Kawada, Y., Etoh, H., Matsuda, T., Kimura-Koyanagi, M., Hashimoto, N., Sakahara, M., Fujimoto, W., Takahashi, H., Ueda, S., Hosooka, T., Satoh, T., Inoue, H., Matsumoto, M., Aiba, A., Kasuga, M., & Kido, Y. (2013). Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin. Diabetologia, 56(5), 1088–1097. https://doi.org/10.1007/s00125-013-2849-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sylow, L., Jensen, T. E., Kleinert, M., Højlund, K., Kiens, B., Wojtaszewski, J., et al. (2013). Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes, 62(6), 1865–1875. https://doi.org/10.2337/db12-1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Saoudi, A., Kassem, S., Dejean, A., & Gaud, G. (2014). Rho-GTPases as key regulators of T lymphocyte biology. Small GTPases, 5, e983862. https://doi.org/10.4161/sgtp.28208.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of China-Guangdong Joint Fund (U1601229), the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (“Climbing Program” Special Funds, pdjh2020a0218) and and the National Undergraduate Training Program for Innovation and Entrepreneurship (201810560037).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Li-Yan Xu or En-Min Li.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, RJ., Zheng, CW., Chen, WX. et al. Rho GTPases in cancer radiotherapy and metastasis. Cancer Metastasis Rev 39, 1245–1262 (2020). https://doi.org/10.1007/s10555-020-09923-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-020-09923-5

Keywords

Navigation