Abstract
Antimicrobial peptides are the first defense molecules against various organisms such as bacteria, fungi and are produced by different organisms. In this study, we aimed to investigate the anticancer effects of an insect antimicrobial peptide, cryptonin isolated from the hemolymph of cicada, Cryptotympana dubia on malignant melanoma cells. Cryptonin decreased the cell viability in a dose and time-dependent manner and these effects are more in metastatic cells than in other cell lines. The release of LDH from damaged cells and the detection of HMGB1 in cell culture media after peptide treatment indicated that cryptonin could induce cell necrosis and this cell death may activate an immune response. The peptide also increased the necrotic cell nucleus stained with ethidium bromide. According to reactive oxygen species production and mitochondrial membrane depolarization results, the apoptotic effect of the peptide was low in melanoma cells. Although the peptide killed the keratinocytes in vitro, cryptonin or cryptonin- derived peptide may have potential use in the treatment of malignant melanoma.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
American Cancer Society (2022) Cancer Facts & Statistics. Available from https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf. Accessed 26 October 2022
Anghel R, Jitaru D, Badescu L, Ciocoiu M, Badescu M (2014) The cytotoxic effect of Cecropin A and Cecropin B on the MDAMB-231 and M14K tumour cell lines. J Biomed Sci. https://doi.org/10.4236/jbise.2014.78052. Eng7:504 – 15
Austin E, Mamalis A, Ho D, Jagdeo J (2017) Laser and light-based therapy for cutaneous and soft-tissue metastases of malignant melanoma: a systematic review. Arch Dermatol Res 309:229–242. https://doi.org/10.1007/s00403-017-1720-9
Batus M, Waheed S, Ruby C, Petersen L, Bines SD, Kaufman HL (2013) Optimal management of metastatic melanoma: current strategies and future directions. Am J Clin Dermatol 14:179–194. https://doi.org/10.1007/s40257-013-0025-9
Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220:35–46. https://doi.org/10.1111/j.1600-065X.2007.00574.x
Camilio KA, Wang MY, Mauseth B (2019) Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model. Breast Cancer Res 21:9. https://doi.org/10.1186/s13058-018-1092-x
Cerón JM, Contreras-Moreno J, Puertollano E, de Cienfuegos G, Puertollano MA, de Pablo MA (2010) The antimicrobial peptide cecropin A induces caspase-independent cell death in human promyelocytic leukemia cells. Peptides 31:1494–1503. https://doi.org/10.1016/j.peptides.2010.05.008
Chen YQ, Min C, Sang M, Han YY, Ma X, Xue XQ, Zhang SQ (2010) A cationic amphiphilic peptide ABP-CM4 exhibits selective cytotoxicity against leukemia cells. Peptides 31:1504–1510. https://doi.org/10.1016/j.peptides.2010.05.010
de Azevedo RA, Figueiredo CR, Ferreira AK, Matsuo AL, Massaoka MH, Girola N, Auada AV, Farias CF, Pasqualoto KF, Rodrigues CP, Barbuto JA, Levy D, Bydlowski SP, de Sá-Junior PL, Travassos LR, Lebrun I (2015) Mastoparan induces apoptosis in B16F10-Nex2 melanoma cells via the intrinsic mitochondrial pathway and displays antitumor activity in vivo. Peptides 68:113–119. https://doi.org/10.1016/j.peptides.2014.09.024
Ditsworth D, Zong WX, Thompson CB (2007) Activation of poly (ADP)-ribose polymerase (PARP-1) induces release of the pro-inflammatory mediator HMGB1 from the nucleus. J Biol Chem 282:17845–17854. https://doi.org/10.1074/jbc.M701465200
Domingues B, Lopes JM, Soares P, Pópulo H (2018) Melanoma treatment in review. Immunotargets Ther 7:35–49. https://doi.org/10.2147/ITT.S134842
Eggermont AM, Spatz A, Robert C (2014) Cutaneous melanoma. Lancet 383:816–827. https://doi.org/10.1016/S0140-6736(13)60802-8
Eike LM, Mauseth B, Camilio KA, Rekdal Ø, Sveinbjørnsson B (2016) The Cytolytic Amphipathic β(2,2)-Amino acid LTX-401 induces DAMP Release in Melanoma cells and causes complete regression of B16 melanoma. PLoS ONE 11:e0148980. https://doi.org/10.1371/journal.pone.0148980
Fogh J, Bean MA, Brüggen J, Fogh H, Fogh JM, Hammar SP, Kodera Y, Loveless JD, Sorg C, Wright WC (1978) Comparison of a human tumor cell line before and after growth in the nude mouse. In: Fogh J, Giovanella B (eds) The nude mouse in experimental and clinical research. Academic Press, New York, pp 215–234
Gautam A, Kapoor P, Chaudhary K, Kumar R, Open Source Drug Discovery Consortium, Raghava GP (2014) Tumor homing peptides as molecular probes for cancer therapeutics, diagnostics and theranostics. Curr Med Chem 21:2367–2391. https://doi.org/10.2174/0929867321666140217122100
Gazit E, Boman A, Boman HG, Shai Y (1995) Interaction of the mammalian antibacterial peptide cecropin P1 with phospholipid vesicles. Biochemistry 34:11479–11488. https://doi.org/10.1021/bi00036a021
Gerashchenko O, Zhuravel E, Skachkova O, Khranovska N, Pushkarev V, Pogrebnoy P, Soldatkina M (2014) Involvement of human beta-defensin-2 in regulation of malignant potential of cultured human melanoma cells. Exp Oncol 36:17–23
Giuliani A, Pirri G, Bozzi A, Di Giulio A, Aschi M, Rinaldi AC (2008) Antimicrobial peptides: natural templates for synthetic membrane-active compounds. Cell Mol Life Sci 65:2450–2460. https://doi.org/10.1007/s00018-008-8188-x
Hancock RE (1997) Peptide antibiotics. Lancet 349:418–422. https://doi.org/10.1016/S0140-6736(97)80051-80057
Hancock RE, Haney EF, Gill EE (2016) The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol 16:321–334. https://doi.org/10.1038/nri.2016.29
Hilchie AL, Hoskin DW (2010) The application of cationic antimicrobial peptides in cancer treatment: laboratory investigations and clinical potential. In: Fialho AM, Chakrabarty A (eds) Emerging cancer therapy: microbial approaches and biotechnological tools. Wiley, Hoboken, pp 309–332
Hilchie AL, Doucette CD, Pinto DM, Patrzykat A, Douglas S, Hoskin DW (2011) Pleurocidin-family cationic antimicrobial peptides are cytolytic for breast carcinoma cells and prevent growth of tumor xenografts. Breast Cancer Res 13:R102. https://doi.org/10.1186/bcr3043
Hoskin DW, Ramamoorthy A (2008) Studies on anticancer activities of antimicrobial peptides. Biochim Biophys Acta 1778(2):357–375. https://doi.org/10.1016/j.bbamem.2007.11.008
Hui L, Leung K, Chen HM (2002) The combined effects of antibacterial peptide cecropin A and anti-cancer agents on leukemia cells. Anticancer Res 22:2811–2816
Huseynzade A (2022) Investigation of possible effects of a new antimicrobial peptides on A549 cell line. Msc Dissertation, Istanbul University
Ju X, Fan D, Kong L, Yang Q, Zhu Y, Zhang S, Su G, Li Y (2021) Antimicrobial peptide Brevinin-1RL1 from frog skin secretion induces apoptosis and necrosis of tumor cells. Molecules 26:2059. https://doi.org/10.3390/molecules26072059
Karikó K, Weissman D, Welsh FA (2004) Inhibition of toll-like receptor and cytokine signaling—a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab 24:1288–1304. https://doi.org/10.1097/01.WCB.0000145666.68576.71
Kim IW, Lee JH, Kwon YN, Yun EY, Nam SH, Ahn MY, Kang DC, Hwang JS (2013) Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis. Int J Oncol 43:622–628. https://doi.org/10.3892/ijo.2013.1973
Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P (2012) Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 12:860–875. https://doi.org/10.1038/nrc3380
Krysko O, Løve Aaes T, Bachert C, Vandenabeele P, Krysko DV (2013) Many faces of DAMPs in cancer therapy. Cell Death Dis 4:e631. https://doi.org/10.1038/cddis.2013.156
Lebel CP, Bondy SC (1990) Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes. Neurochem Int 17:435–440. https://doi.org/10.1016/0197-0186(90)90025-O
Lehmann J, Retz M, Sidhu SS, Suttmann H, Sell M, Paulsen F, Harder J, Unteregger G, Stöckle M (2006) Antitumor activity of the antimicrobial peptide magainin II against bladder cancer cell lines. Eur Urol 50:141–147. https://doi.org/10.1016/j.eururo.2005.12.043
Li J, Wang Y, Liang R, An X, Wang K, Shen G, Tu Y, Zhu J, Tao J (2015) Recent advances in targeted nanoparticles drug delivery to melanoma. Nanomedicine 11:769–794. https://doi.org/10.1016/j.nano.2014.11.006
Lim KJ, Sung BH, Shin JR, Lee YW, Kim DJ, Yang KS, Kim SC (2013) A cancer specific cell-penetrating peptide, BR2, for the efficient delivery of an scFv into cancer cells. PLoS ONE 8:e66084. https://doi.org/10.1371/journal.pone.0066084
Mader JS, Hoskin DW (2006) Cationic antimicrobial peptides as novel cytotoxic agents for cancer treatment. Expert Opin Investig Drugs 15:933–946. https://doi.org/10.1517/13543784.15.8.933
Moran B, Silva R, Perry AS, Gallagher WM (2018) Epigenetics of malignant melanoma. Semin Cancer Biol 51:80–88. https://doi.org/10.1016/j.semcancer.2017.10.006
Oren Z, Shai Y (1998) Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers 47:451–463.
Oren Z, Lerman JC, Gudmundsson GH, Agerberth B, Shai Y (1999) Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem J 341:501–513. https://doi.org/10.1042/bj3410501
Papo N, Shai Y (2003) New lytic peptides based on the D,L-amphipathic helix motif preferentially kill tumor cells compared to normal cells. Biochemistry 42:9346–9354. https://doi.org/10.1021/bi027212o
Park DS, Leem JY, Suh EY, Hur JH, Oh HW, Park HY (2007) Isolation and functional analysis of a 24-residue linear alpha-helical antimicrobial peptide from korean blackish cicada, Cryptotympana dubia (Homoptera). Arch Insect Biochem Physiol 66:204–213. https://doi.org/10.1002/arch.20213
Piris A, Mihm MC Jr, Hoang MP (2015) BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations. Hum Pathol 46:239–245. https://doi.org/10.1016/j.humpath.2014.10.015
Rodrigues EG, Dobroff AS, Cavarsan CF, Paschoalin T, Nimrichter L, Mortara RA, Santos EL, Fázio MA, Miranda A, Daffre S, Travassos LR (2008) Effective topical treatment of subcutaneous murine B16F10-Nex2 melanoma by the antimicrobial peptide gomesin. Neoplasia 10:61–68. https://doi.org/10.1593/neo.07885
Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M, …, Manfredi AA (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5:825–830. https://doi.org/10.1038/sj.embor.7400205
Sancar S, Bolkent S (2022) Cyclic dodecapeptide induces cell death through membrane–peptide interactions in breast cancer cells. Int J Pept Res Ther 28:67. https://doi.org/10.1007/s10989-022-10369-2
Sancar- Bas S (2013) The effects of some antimicrobial peptides on breast cancer cell lines. PhD Dissertation, Istanbul University
Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA (2009) Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy. Mol Cancer Ther 8:1292–1304. https://doi.org/10.1158/1535-7163.MCT-08-1030
Suttmann H, Retz M, Paulsen F, Harder J, Zwergel U, Kamradt J, Wullich B, Unteregger G, Stöckle M, Lehmann J (2008) Antimicrobial peptides of the Cecropin-family show potent antitumor activity against bladder cancer cells. BMC Urol 8:5. https://doi.org/10.1186/1471-2490-8-5
Tonk M, Vilcinskas A, Rahnamaeian M (2016) Insect antimicrobial peptides: potential tools for the prevention of skin cancer. Appl Microbiol Biotechnol 100:7397–7405. https://doi.org/10.1007/s00253-016-7718-y
van Zoggel H, Carpentier G, Dos Santos C, Hamma-Kourbali Y, Courty J, Amiche M et al (2012) Antitumor and angiostatic activities of the antimicrobial peptide dermaseptin B2. PLoS ONE 7:e44351. https://doi.org/10.1371/journal.pone.0044351
Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Cook M, Dhomen N, Marais R (2014) Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. Nature 511:478–482. https://doi.org/10.1038/nature13298
Wang KR, Zhang BZ, Zhang W, Yan JX, Li J, Wang R (2008) Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29:963–968. https://doi.org/10.1016/j.peptides.2008.01.015
Wang C, Chen T, Zhang N, Yang M, Li B, Lü X, Cao X, Ling C (2009) Melittin, a major component of bee venom, sensitizes human hepatocellular carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by activating CaMKII-TAK1-JNK/p38 and inhibiting IkappaBalpha kinase-NFkappaB. J Biol Chem 284(6):3804–3813. https://doi.org/10.1074/jbc.M807191200
Wang C, Tian LL, Li S, Li HB, Zhou Y, Wang H, …, Shang DJ (2013) Rapid cytotoxicity of antimicrobial peptide tempoprin-1CEa in breast cancer cells through membrane destruction and intracellular calcium mechanism. PLoS ONE 8(4):e60462. https://doi.org/10.1371/journal.pone.0060462
Wu JM, Jan PS, Yu HC, Haung HY, Fang HJ, Chang YI, Cheng JW, Chen HM (2009) Structure and function of a custom anticancer peptide, CB1a. Peptides 30:839–848. https://doi.org/10.1016/j.peptides.2009.02.004
Wu YL, **a LJ, Li JY, Zhang FC (2015) CecropinXJ inhibits the proliferation of human gastric cancer BGC823 cells and induces cell death in vitro and in vivo. Int J Oncol 46:2181–2193. https://doi.org/10.3892/ijo.2015.2933
**a L, Zhang F, Liu Z, Ma J, Yang J (2013) Expression and characterization of cecropin XJ, a bioactive antimicrobial peptide from Bombyx mori (Bombycidae, Lepidoptera) in Escherichia coli. Exp Ther Med 5:1745–1751. https://doi.org/10.3892/etm.2013.1056
**a L, Wu Y, Kang S, Ma J, Yang J, Zhang F (2014) Cecropin XJ, a silkworm antimicrobial peptide, induces cytoskeleton disruption in esophageal carcinoma cells. Acta Biochim Biophys Sin (Shanghai) 46:867–876. https://doi.org/10.1093/abbs/gmu070
Ye JS, Zheng XJ, Leung KW, Chen HM, Sheu FS (2004) Induction of transient ion channel-like pores in a cancer cell by antibiotic peptide. J Biochem 136:255–259. https://doi.org/10.1093/jb/mvh114
Acknowledgements
G. Torkay and T. Çan would like to acknowledge the financial supports from the Scientific and Technological Research Council of Turkey (TUBITAK) 2210/A General Domestic Graduate Scholarship Program (App No:1649B022101483 and 1649B022113419).
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SS designed the main idea and experiments, did the experiments, evaluated the experimental results statistically, wrote the main manuscript text, found the foundation and GT and TC contributed to the experiments. All authors reviewed the manuscript.
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Sancar, S., Torkay, G. & Çan, T. A Cicada Antimicrobial Peptide, Cryptonin, Exhibits Potent Antitumor Activity by Necrosis on Human Melanoma Cells. Int J Pept Res Ther 29, 68 (2023). https://doi.org/10.1007/s10989-023-10540-3
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DOI: https://doi.org/10.1007/s10989-023-10540-3