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The molecular mechanisms of vulpinic acid induced programmed cell death in melanoma

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Abstract

Backgrounds

Malignant melanoma is an aggressive skin tumor with a rapidly increasing incidence and there is not yet a successful treatment strategy. Vulpinic acid (VA) is derived from secondary metabolites from lichen species. In the current study, we, for the first time, investigated the anti-cancer effects of VA and the underlying mechanism VA induced programmed cell death in melanoma.

Methods

The anti-cancer effects of VA on melanoma cells were evaluated by the xCELLigence system, flow cytometry, caspase-3 activity and RT-PCR analysis.

Results

Our results showed that VA had a strong anti-proliferative effect on A-375 melanoma cells without damaging human epidermal melanocyte cells. Additionally, VA promoted apoptotic cell death through G2/M arrest and the activation of both intrinsic and extrinsic apoptosis pathways according to the analysis of 88 genes associated with apoptosis by qRT-PCR.

Conclusions

Our findings suggest that VA could become an alternative topical and transdermal treatment strategy in the treatment of maligned melanoma cancer. However, further investigations are needed to assess the underlying molecular mechanism of VA mediated apoptotic cell death in the treatment of melanoma.

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References

  1. O’Neill CH, Scoggins CR (2019) Melanoma. J Surg Oncol 120(5):873–881. https://doi.org/10.1002/jso.25604

    Article  PubMed  Google Scholar 

  2. American Cancer Society (2019) Cancer facts & Fig. 2019. Atlanta: American Cancer Society 1 – 4

  3. Lo JA, Fisher DE (2014) The melanoma revolution: from UV carcinogenesis to a new era in therapeutics. Science 346(6212):945–949. https://doi.org/10.1126/science.1253735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jenkins RW, Fisher DE (2021) Treatment of Advanced Melanoma in 2020 and Beyond. J Invest Dermatol 141(1):23–31. https://doi.org/10.1016/j.jid.2020.03.943

    Article  CAS  PubMed  Google Scholar 

  5. Micali G, Lacarrubba F, Nasca MR, Schwartz RA (2014) Topical pharmacotherapy for skin cancer: part I. Pharmacology. J Am Acad Dermatol 70(6):965. https://doi.org/10.1016/j.jaad.2013.12.045. .e1 – 978

    Article  CAS  PubMed  Google Scholar 

  6. Abbas K, Qadir M, Anwar S (2019) The Role of Melanin in Skin Cancer. Crit Rev Eukaryot Gene Expr 29(1):17–24. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2018024980

    Article  PubMed  Google Scholar 

  7. Gray-Schopfer V, Wellbrock C, Marais R (2007) Melanoma biology and new targeted therapy. Nature 445(7130):851–857. https://doi.org/10.1038/nature05661

    Article  CAS  PubMed  Google Scholar 

  8. Hammerová J, Uldrijan S, Táborská E, Slaninová I (2011) Benzo[c]phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. J Dermatol Sci 62(1):22–35. https://doi.org/10.1016/j.jdermsci.2011.01.006

    Article  CAS  PubMed  Google Scholar 

  9. Yi SA, Nam KH, Kim S, So HM, Ryoo R, Han JW, Kim KH, Lee J (2019) Vulpinic Acid Controls Stem Cell Fate toward Osteogenesis and Adipogenesis. Genes 11(1):18. https://doi.org/10.3390/genes11010018

    Article  CAS  PubMed Central  Google Scholar 

  10. [Kılıç N, Derici MK, Büyük İ, Aydın SS, Aras S, Cansaran-Duman D (2018) Evaluation of in vitro Anticancer Activity of Vulpinic Acid and its Apoptotic Potential Using Gene Expression and Protein Analysis. Indian J Pharm Edu Res 52(4):626–634. https://doi.org/10.5530/ijper.52.4.73

    Article  CAS  Google Scholar 

  11. Kwon Y, Cha J, Chiang J, Tran G, Giaever G, Nislow C, Hur JS, Kwak YS (2016) A chemogenomic approach to understand the antifungal action of Lichen-derived vulpinic acid. J Appl Microbiol 121(6):1580–1591. https://doi.org/10.1111/jam.13300

    Article  CAS  PubMed  Google Scholar 

  12. Kwon HY, Kim KS, Baik JS, Moon HI, Lee JW, Kim CH et al (2013) Tryptoplide-Mediated Apoptosis by Suppression of Focal Adhesion Kinase through Extrinsic and Intrinsic Pathways in Human Melanoma Cells. Evid Based Compl Alter Med 172548. https://doi.org/10.1155/2013/172548

  13. Shrestha G, Thompson A, Robison R, St Clair LL (2016) Letharia vulpina, a vulpinic acid containing lichen, targets cell membrane and cell division processes in methicillin-resistant Staphylococcus aureus. Pharm Biol 54(3):413–418. https://doi.org/10.3109/13880209.2015.1038754

    Article  CAS  PubMed  Google Scholar 

  14. Rundel PW (1978) The ecological role of secondary lichen substances. Biochem Syst Ecol 6:157–170

    Article  CAS  Google Scholar 

  15. Molnár K, Farkas E (2010) Current results on biological activities of lichen secondary metabolites: a review. Z Naturforsch C J Biosci 65(3–4):157–173. https://doi.org/10.1515/znc-2010-3-401

    Article  PubMed  Google Scholar 

  16. Koparal AT (2015) Anti-angiogenic and antiproliferative properties of the lichen substances (-)-usnic acid and vulpinic acid. Z Naturforsch C J Biosci 70(5–6):159–164. https://doi.org/10.1515/znc-2014-4178

    Article  CAS  PubMed  Google Scholar 

  17. Kılıç N, Aras S, Cansaran-Duman D (2018) Determination of Vulpinic Acid Effect on Apoptosis and mRNA Expression Levels in Breast Cancer Cell Lines. Anticancer Agents Med Chem 18(14):2032–2041. https://doi.org/10.2174/1871520618666180903101803

    Article  CAS  PubMed  Google Scholar 

  18. Kim S, So H, Roh H, Kim J, Yu J, Lee S et al (2017) Vulpinic acid contributes to the cytotoxicity of Pulveroboletus rhubarbelii to human cancer cells by inducing apoptosis. RSC Adv 7:35297–35304

    Article  CAS  Google Scholar 

  19. Adewale FO, Basiru AO, Ayorinde OO, Israel OI, Oluwafemi OA (2017) Regulation of apoptotic and necroptotic cell death in skin cancer. J Cancer Biol Res 5(4):1108

    Google Scholar 

  20. Broussard L, Howland A, Ryu S, Song K, Norris D, Armstrong CA, Song PI (2018) Melanoma Cell Death Mechanisms. Chonnam Med J 54(3):135–142. https://doi.org/10.4068/cmj.2018.54.3.135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mattia G, Puglisi R, Ascione B, Malorni W, Carè A, Matarrese P (2018) Cell death-based treatments of melanoma:conventional treatments and new therapeutic strategies. Cell Death Dis 9(2):112. https://doi.org/10.1038/s41419-017-0059-7

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hussein MR, Haemel AK, Wood GS (2003) Apoptosis and melanoma: molecular mechanisms. J Pathol 199(3):275–288. https://doi.org/10.1002/path.1300

    Article  CAS  PubMed  Google Scholar 

  23. Galluzzi L, Vitale I, Aaronson SA et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death Differ 2018. Cell Death Differ 25:486–541. https://doi.org/10.1038/s41418-017-0012-4

    Article  PubMed  PubMed Central  Google Scholar 

  24. Karaosmanoglu O, Sivas H, Tay T, Turkish A (2015) The vitro investigation of cytotoxic and apoptotic effects vulpinic acid on normal and cancer cells. J Biotechnol 208:S95

    Article  Google Scholar 

  25. Varol M, Turk A, Candan M, Tay T, Koparal AT (2016) Photoprotective Activity of Vulpinic and Gyrophoric Acids Toward Ultraviolet B-Induced Damage in Human Keratinocytes. Phytother Res 30(1):9–15. https://doi.org/10.1002/ptr.5493

    Article  CAS  PubMed  Google Scholar 

  26. Cansaran-Duman D, Guney Eskiler G, Colak B, Sozen Kucukkara E (2021) Vulpinic acid as a natural compound inhibits the proliferation of metastatic prostate cancer cells by inducing apoptosis. Mol Biol Rep 48(8):6025–6034. https://doi.org/10.1007/s11033-021-06605-5

    Article  CAS  PubMed  Google Scholar 

  27. Hamsa TP, Kuttan G (2011) Harmine activates intrinsic and extrinsic pathways of apoptosis in B16F-10 melanoma. Chin Med 6(1):11. https://doi.org/10.1186/1749-8546-6-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ramirez M, Salvesen GS (2018) A primary on caspase mechanisms. Semin Cell Dev Biol 82:79–85. https://doi.org/10.1016/j.semcdb.2018.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Arch RH, Gedrich RW, Thompson CB (1998) Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulate life and death. Genes Dev 12:2821–2830. https://doi.org/10.1101/gad.12.18.2821

    Article  CAS  PubMed  Google Scholar 

  30. Luo Z, Zhang X, Zeng W, Water J, Yang K, Lu L et al (2016) TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget 7(6):7179–7192. https://doi.org/10.18632/oncotarget.6886

    Article  PubMed  PubMed Central  Google Scholar 

  31. Beroukhim R, Mermel CH, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905. https://doi.org/10.1038/nature08822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Starczynowski DT, Lockwood WW, Deléhouzée S, Chari R, Wegrzyn J, Fuller M, Tsao MS et al (2011) TRAF6 is an amplified oncogene bridging the RAS and NF-εB pathways in human lung cancer. J Clin Invest 121(10):4095–4105. https://doi.org/10.1172/JCI58818

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Meng Q, Zheng M, Liu H, Song C, Zhang W, Yan J, Qin L, Liu X (2012) TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. Mol Cell Biochem 371(1–2):177–186. https://doi.org/10.1007/s11010-012-1434-4

    Article  CAS  PubMed  Google Scholar 

  34. Chung JY, Park YC, Eat H, Wu H (2002) All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 115(Pt 4):679–688

    Article  CAS  Google Scholar 

  35. Rajandram R, Bennett NC, Wang Z, Perry-Keene J, Vesey DA, Johnson DW, Gobe GC (2012) Patient samples of renal cell carcinoma show reduced expression of TRAF1 compared with normal kidney and functional studies in vitro indicate TRAF1 promotes apoptosis: potential for targeted therapy. Pathology 44(5):453–459. https://doi.org/10.1097/PAT.0b013e3283557748

    Article  CAS  PubMed  Google Scholar 

  36. Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmukle AC, Davidson AJ, e (2009) TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (tnf) to efficiently activate nf-{kappa}b and to prevent tnf-induced apoptosis. J Biol Chem 284(51):35906–35915. https://doi.org/10.1074/jbc.M109.072256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Elbadawy M, Usui T, Yamawaki H, Sasaki K (2018) Novel functions of death-associated protein kinases through mitogen-activated protein kinase-related signals. Int J Mol Sci 19(10):3031. https://doi.org/10.3390/ijms19103031

    Article  CAS  PubMed Central  Google Scholar 

  38. van den Oord JJ, Maes A, Stas M, Nuyts J, Battocchio S, Kasran A, De Wolf-Peeters C (1996) CD40 is a prognostic marker in primary cutaneous malignant melanoma. Am J Pathol 149(6):1953

    PubMed  PubMed Central  Google Scholar 

  39. Georgopoulos NT, Steele LP, Thomson MJ, Selby PJ, Southgate J, Trejdosiewicz LK (2006) A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation. Cell Death Differ 13(10):1789–1801. https://doi.org/10.1038/sj.cdd.4401859

    Article  CAS  PubMed  Google Scholar 

  40. Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30(1):87. https://doi.org/10.1186/1756-9966-30-87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Akl H, Vervloessem T, Kiwiluoto S, Bittremieux M, Parys JB, De Smedt H, Bultynck G (2014) A dual role for the anti-apoptoctic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. Biochim Biophys Acta 1843(10):2240–2252. https://doi.org/10.1016/j.bbamcr.2014.04.017

    Article  CAS  PubMed  Google Scholar 

  42. Lindqvist LM, Simon AK, Baehrecke EH (2015) Current questions and possible controversies in autophagy. Cell Death Discov 1:15036. https://doi.org/10.1038/cddiscovery.2015.36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hatok J, Racay P (2016) Bcl-2 family proteins: master regulators of cell survival. Biomol Concepts 7(4):259–270. https://doi.org/10.1515/bmc-2016-0015

    Article  CAS  PubMed  Google Scholar 

  44. Shakeri R, Kheirollahi A, Davoodi J (2017) Apaf-1: Regulation and function in cell death. Biochimie 135:111–125. https://doi.org/10.1016/j.biochi.2017.02.001

    Article  CAS  PubMed  Google Scholar 

  45. Steeland S, Libert C, Vandenbroucke RE (2018) A new venue of TNF targeting. Int J Mol Sci 19(5):1442. https://doi.org/10.3390/ijms19051442

    Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

This research was partly supported by the research grants from the Scientific and Technological Research Council of Turkey (TUBITAK, Project no. 216S583).

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Authors and Affiliations

  1. Biotechnology Institute, Ankara University, Keçiören, Ankara, Turkey

    Sevcan Yangın & Demet Cansaran-Duman

  2. Department of Medical Biology, Faculty of Medicine, Sakarya University, Sakarya, Turkey

    Gamze Guney Eskiler

  3. Faculty of Science, Biology Department, Ankara University, Ankara, Turkey

    Sümer Aras

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  1. Sevcan Yangın
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  2. Demet Cansaran-Duman
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  3. Gamze Guney Eskiler
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Contributions

Conceptualization, D.C.D.; investigation, S.Y.; writing—original draft preparation, S.Y., G.G.E., S.A.; writing—review and editing, D.C.D.; supervision, D.C.D. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Demet Cansaran-Duman.

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Yangın, S., Cansaran-Duman, D., Eskiler, G.G. et al. The molecular mechanisms of vulpinic acid induced programmed cell death in melanoma. Mol Biol Rep 49, 8273–8280 (2022). https://doi.org/10.1007/s11033-022-07619-3

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  • DOI: https://doi.org/10.1007/s11033-022-07619-3

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