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HSP70 desensitizes osteosarcoma cells to baicalein and protects cells from undergoing apoptosis

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Abstract

Baicalein is a new drug that has shown promising anti-cancer effects against a broad spectrum of tumors. However, the potential effect on osteosarcoma cells and the mechanisms involved are still largely unknown. Resistance to chemotherapy remains a major obstacle in cancer therapy. Therefore, the aim of the present study was to investigate the anti-tumor effect of baicalein on human osteosarcoma cancer cells and the molecular mechanism involved, as well as identify possible mechanisms of drug resistance. Our results revealed that baicalein-induced apoptosis in osteosarcoma cells was via a mitochondrial pathway involving both caspase-dependent and independent mechanisms. Notably, baicalein treatment upregulated the expression of HSP70, which partially prevented human osteosarcoma cells from undergoing apoptosis. Moreover, it was revealed that HSP70 expression decreased the sensitivity of osteosarcoma cells to baicalein via activation of PI3K/AKT and MAPK/ERK pathways. These results suggest that targeting HSP70-mediated drug resistance, in combination with chemotherapy drugs, may provide novel therapeutic opportunities.

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Abbreviations

Baicalein:

5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one

MTT:

3-[4,5-dimethylthiazol-2-y]-2,5-diphenyltetrazolium bromide

MAPK:

Mitogen-activated protein kinase

KNK437:

N-formyl-3,4-methylenedioxy-benzylidene-g-butyrolactam

HSP70:

Heat shock protein 70

Cyto-c:

Cytochrome c

PI:

Propidium iodide

ERK:

Extracellular-signal-regulated kinase

PI3K:

Phosphoinositide 3-kinase

ROS:

Reactive oxygen species

AIF:

Apoptosis-inducing factor

NAC:

N-acetyl-l-cysteine

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethyl sulfoxide

PI:

Propidium iodide

References

  1. Janeway KA, Barkauskas DA, Krailo MD, Meyers PA, Schwartz CL, Ebb DH, Seibel NL, Grier HE, Gorlick R, Marina N (2012) Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children’s Oncology Group. Cancer 118(18):4597–4605

    Article  PubMed Central  PubMed  Google Scholar 

  2. Gobin B, Moriceau G, Ory B, Charrier C, Brion R, Blanchard F, Redini F, Heymann D (2014) Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models. PLoS One 9(3):e90795

    Article  PubMed Central  PubMed  Google Scholar 

  3. Arias JL (2011) Drug targeting strategies in cancer treatment: an overview. Mini Rev Med Chem 11(1):1–17

    Article  CAS  PubMed  Google Scholar 

  4. De Santi C, Pietrabissa A, Mosca F, Pacifici GM (2002) Methylation of quercetin and fisetin, flavonoids widely distributed in edible vegetables, fruits and wine, by human liver. Int J Clin Pharmacol Ther 40(5):207–212

    Article  PubMed  Google Scholar 

  5. Czaplińska M, Czepas J, Gwoździński K (2012) Structure, antioxidative and anticancer properties of flavonoids. Postepy Biochem 58(3):235–244

    PubMed  Google Scholar 

  6. Donald G, Hertzer K, Eibl G (2012) Baicalein: an intriguing therapeutic phytochemical in pancreatic cancer. Curr Drug Targets 13(14):1772–1776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kim SJ, Kim HJ, Kim HR, Lee SH, Cho SD, Choi CS, Nam JS, Jung JY (2012) Antitumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Mol Med Rep 6(6):1443–1449

    CAS  PubMed  Google Scholar 

  8. Wang CZ, Li XL, Wang QF, Mehendale SR, Yuan CS (2010) Selective fraction of Scutellaria baicalensis and its chemopreventive effects on MCF-7 human breast cancer cells. Phytomedicine 17(1):63–68

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Zhang Y, Song L, Cai L, Wei R, Hu H, ** W (2013) Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells. Food Chem Toxicol 53:325–333

    Article  CAS  PubMed  Google Scholar 

  10. Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325(2):117–124

    Article  CAS  PubMed  Google Scholar 

  11. Sliutz G, Karlseder J, Tempfer C, Orel L, Holzer G, Simon MM (1996) Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: implication of quercetin as sensitiser in chemotherapy. Br J Cancer 74(2):172–177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Wessel D, Flu¨gge UI (1984) A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem 138:141–143

    Article  CAS  PubMed  Google Scholar 

  13. Schmid TE, Multhoff G (2012) Radiation-induced stress proteins: the role of heat shock proteins (HSP) in anti-tumor responses. Curr Med Chem 19(12):1765–1770

    Article  CAS  PubMed  Google Scholar 

  14. Choi YJ, Om JY, Kim NH, Chang JE, Park JH, Kim JY, Lee HJ, Kim SS, Chun W (2013) Heat shock transcription factor-1 suppresses apoptotic cell death and ROS generation in 3-nitropropionic acid-stimulated striatal cells. Mol Cell Biochem 375(1–2):59–67

    CAS  PubMed  Google Scholar 

  15. Yamashima T (2012) Hsp70.1 and related lysosomal factors for necrotic neuronal death. J Neurochem 120(4):477–494

    Article  CAS  PubMed  Google Scholar 

  16. Lee Youn Ju, Kim Nam-Yi, Suh Young-Ah, Lee ChuHee (2011) Involvement of ROS in curcumin-induced autophagic cell death. Korean J Physiol Pharmacol 15(1):1–7

    Article  PubMed Central  PubMed  Google Scholar 

  17. Yoshihisa Y, Hassan MA, Furusawa Y, Tabuchi Y, Kondo T, Shimizu T (2012) Alkannin, HSP70 inducer, protects against UVB-induced apoptosis in human keratinocytes. PLoS One 7(10):e47903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Ma GZ, Liu CH, Wei B, Qiao J, Lu T, Wei HC, Chen HD, He CD (2013) Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation. Inflammation 36(2):457–467

    Article  CAS  PubMed  Google Scholar 

  19. Huang Y, Tsang SY, Yao X, Chen ZY (2005) Biological properties of baicalein in cardiovascular system. Curr Drug Targets Cardiovasc Haematol Disord 5(2):177–184

    Article  CAS  PubMed  Google Scholar 

  20. Sithisarn P, Michaelis M, Schubert-Zsilavecz M, Cinatl J Jr (2013) Differential antiviral and anti-inflammatory mechanisms of the flavonoids biochanin A and baicalein in H5N1 influenza A virus-infected cells. Antivir Res 97(1):41–48

    Article  CAS  PubMed  Google Scholar 

  21. Takahashi H, Chen MC, Pham H, Angst E, King JC, Park J, Brovman EY, Ishiguro H, Harris DM, Reber HA, Hines OJ, Gukovskaya AS, Go VL, Eibl G (2011) Baicalein, a component of Scutellaria baicalensis, induces apoptosis by Mcl-1 down-regulation in human pancreatic cancer cells. Biochim Biophys Acta 1813(8):1465–1474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chen J, Li Z, Chen AY, Ye X, Luo H, Rankin GO, Chen YC (2013) Inhibitory effect of baicalin and baicalein on ovarian cancer cells. Int J Mol Sci 14(3):6012–6025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Veresov VG, Davidovskii AI (2009) Activation of Bax by joint action of tBid and mitochondrial outer membrane: Monte Carlo simulations. Eur Biophys J 38(7):941–960

    Article  CAS  PubMed  Google Scholar 

  24. Haneef J, Parvathy M, Thankayyan RSK, Sithul H, Sreeharshan S (2012) Bax translocation mediated mitochondrial apoptosis and caspase dependent photosensitizing effect of Ficus religiosa on cancer cells. PLoS One 7(7):e40055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Leprêtre C, Tchakarska G, Blibech H, Lebon C, Torriglia A (2013) Apoptosis-inducing factor (AIF) and leukocyte elastase inhibitor/L-DNase II (LEI/LDNaseII), can interact to conduct caspase-independent cell death. Apoptosis 18(9):1048–1059

    Article  PubMed  Google Scholar 

  26. Rauch JN, Gestwicki JE (2014) Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. J Biol Chem 289(3):1402–1414

    Article  CAS  PubMed  Google Scholar 

  27. Matokanovic M, Barisic K, Filipovic-Grcic J, Maysinger D (2013) Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90. Eur J Pharm Sci 50(1):149–158

    Article  CAS  PubMed  Google Scholar 

  28. Yuan J, Kashiwagi S, Reeves P, Nezivar J, Yang Y, Arrifin NH, Nguyen M, Jean-Mary G, Tong X, Uppal P et al (2014) A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma. J Hematol Oncol 7(1):15

    Article  PubMed Central  PubMed  Google Scholar 

  29. Rérole AL, Gobbo J, De Thonel A, Schmitt E, de Pais Barros JP, Hammann A, Lanneau D, Fourmaux E, Deminov O, Deminov O, Micheau O, Lagrost L, Colas P, Kroemer G, Garrido C (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71(2):484–495

    Article  PubMed  Google Scholar 

  30. Hall L, Martinus RD (2013) Hyperglycaemia and oxidative stress upregulate HSP60 and HSP70 expression in HeLa cells. Springerplus 3(2):431

    Article  Google Scholar 

  31. Endo H, Yano M, Okumura Y, Kido H (2014) Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70. Cell Death Dis 30(5):e1027

    Article  Google Scholar 

  32. Plotkin LI, Bellido T (2001) Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ERK pathway: a gap junction-independent action of connexin43. Cell Commun Adhes 8(4–6):377–382

    Article  CAS  PubMed  Google Scholar 

  33. Bezler M, Hengstler JG, Ullrich A (2012) Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells. Mol Oncol 6(5):516–529

    Article  CAS  PubMed  Google Scholar 

  34. Padwad YS, Mishra KP, Jain M, Chanda S, Ganju L (2010) Dengue virus infection activates cellular chaperone Hsp70 in THP-1 cells: downregulation of Hsp70 by siRNA revealed decreased viral replication. Viral Immunol 23(6):557–565

    Article  CAS  PubMed  Google Scholar 

  35. Tang FQ, Duan CJ, Huang DM, Wang WW, **e CL, Meng JJ, Wang L, Jiang HY, Feng DY, Wu SH, Gu HH, Li MY, Deng FL, Gong ZJ, Zhou H, Xu YH, Tan C, Zhang X (2009) Cao Y.HSP70 and mucin 5B: novel protein targets of N,N′-dinitrosopiperazine-induced nasopharyngeal tumorigenesis. Cancer Sci 100(2):216–224

    Article  CAS  PubMed  Google Scholar 

  36. Ciocca DR, Arrigo AP, Calderwood SK (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87(1):19–48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Hatfield MP, Lovas S (2012) Role of Hsp70 in cancer growth and survival. Protein Pept Lett 19(6):616–624

    Article  CAS  PubMed  Google Scholar 

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Conflicts of interest

Lianghua Ding, Shuanghua He, **aoliang Sun have no conflicts of interest.

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Authors and Affiliations

  1. Department of Orthopedics, The Third Affiliated Hospital of Suzhou University, No 185 Juqian Street, Changzhou, 213003, China

    Lianghua Ding, Shuanghua He & **aoliang Sun

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  1. Lianghua Ding
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Correspondence to **aoliang Sun.

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Ding, L., He, S. & Sun, X. HSP70 desensitizes osteosarcoma cells to baicalein and protects cells from undergoing apoptosis. Apoptosis 19, 1269–1280 (2014). https://doi.org/10.1007/s10495-014-0995-y

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  • DOI: https://doi.org/10.1007/s10495-014-0995-y

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