Ercan CACAN

8082

Kemoreziztant rahim kanseri hücrelerinin TRAIL ve FAS aracılı apoptoz duyarlılıklarının radyasyon ile arttırılması

Amaç: Ölüm reseptörleri, ligandları ile etkileşime girerek apoptotik sinyallerini başlatmaktadır. Ancak over kanserinin gelişimi sürecinde ölüm reseptörlerinin ekspresyonu sıklıkla baskılanmaktadır ve son yıllarda over kanse hücrelerindeki ölüm reseptörlerini baskılanmasının kemoterapötik ilaçlara karşı oluşturulan direnç mekanizmaları ile ilişkili olduğu öne sürülmüştür. Radyoterapi çeşitli kanser tiplerinde yaygın bir tedavi yöntemidir ve düşük dozda iyonize radyasyonun tümörün mikro çevresini etkilediği rapor edilmiştir. Bu çalışmanın amacı ölümcül olmayan iyonize radyasyonun kemorezistan over kanseri hücrelerinde ölüm reseptörlerinin ekspresyonunu değiştirip değiştirmeyeceğinin belirlenmesi ve expresyonu arttırılmış ölüm reseptörlerinin TRAIL ya da FAS ligand FASL aracılı apoptozu arttırıp arttırmayacağının araştırılmasıdır. Yöntem: İlaca dirençli over kanseri hücrelerinde düşük dozlardaki radyasyona maruz bırakıldıktan sonra, kemoterapötik ilacın sisplatin kemosensitif ve kemorezistan over kanseri hücrelerinin canlılığını, ölüm reseptörlerinin hücresel expresyonunu ve FAS veya TRAIL aracılığıyla gerçekleşen apoptoz üzerine etkilerini saptamak amavıyla flow sitometri analizleri kullanılmıştır. Bulgular: İlaçlara duyarlılık gösteren A2780 hücreleri düşük dozdaki ilaca maruz kalmanın ardından ölmeye başladıkları halde yüksek dozdaki sisplatin muamelesinin ardından kemorezistan A2780-AD hücrelerinin büyük bir kısmı canlılığını sürdürmüştür. Sonuçlar 2 Gy yada 5 Gy iyonize radyasyonun çoklu ilaçlara dirençli A2780-AD over kanseri hücrelerinde ölüm reseptörlerinin, FAS ve DR4, expresyonunu arttırdığını göstermiştir. Veriler ölümcül olmayan iyonize radyasyon, kemorezistan over kanseri hücrelerinin FAS ve TRAIL aracılı apoptozu arttırdığını doğrulamıştır. Sonuç: Bu çalışma düşük doz radyasyon tedavisinin doğal olarak tümör hücrelerinin immünojenitisini arttırabileceğini ve anti-tümör immüniteyi indükleyebileceğini akla getirmiştir.
Anahtar Kelimeler:

Over kanseri, kemoterapi, FAS, TRAIL, radyasyon

Enhancing sensitivity of chemoresistant ovarian cancer cells to TRAIL and FAS mediated apoptosis by radiation

Objective: Death receptors initiate apoptotic signals following interaction with their cognate ligands. However, expressions of death receptors are often downregulated during ovarian cancer progression and it has been recently asserted that suppression of death receptors is associated with resistance to chemotherapeutic drugs in ovarian cancer cells. Radiotherapy is a common treatment modality for several cancer types and it has been reported that low-dose ionizing radiation modulates tumor microenvironment. The purpose of the present study is to determine if sublethal ionizing radiation will modulate the expression of common death receptors in chemoresistant ovarian cancer cells and to investigate if reversed expression of death receptors will enhance TRAIL or FAS ligand FASL mediated apoptosis. Methods: Flow cytometry analyses were performed to determine the effects of chemotherapeutic drug, cisplatin, on chemosensitive and chemoresistant ovarian cancer cells viability, cellular expressions of death receptors and TRAIL or FAS mediated apoptosis, following sub-lethal irradiation in drug resistant ovarian cancer cells. Results: The majority of chemoresistant A2780- AD cells remain viable following a high dose of cisplatin treatment, while the drug sensitive A2780 cells started to die following low dose drug exposure. The results have demonstrated that 2 Gy or 5 Gy ionizing radiation enhances expression of death receptors, FAS and DR4, in multi drug resistant A2780-AD ovarian cancer cells. The data further have confirmed that sub-lethal ionizing radiation increases FAS/TRAIL-mediated apoptosis of the chemoresistant ovarian tumor cells. Conclusion: This study has suggested that sublethal radiation treatment may simultaneously increase immunogenicity of tumor cells and the induction of antitumor immunity to chemoresistant ovarian cancer cells.
Keywords:

Ovarian cancer, chemoresistance, FAS, TRAIL, radiation,

PDF

___

  • 1. Smolle E, Taucher V, Haybaeck J. Malignant ascites in ovarian cancer and the role of targeted therapeutics. Anticancer research. 2014;34:1553- 61.
  • 2. McEvoy LM, O’Toole SA, Spillane CD, Martin CM, Gallagher MF, Stordal B, et al. Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer. BMC cancer. 2015;15:547.
  • 3. Muallem MZ, Braicu I, Nassir M, Richter R, Sehouli J, Arsenic R. ERCC1 expression as a predictor of resistance to platinum-based chemotherapy in primary ovarian cancer. Anticancer research. 2014;34:393-9.
  • 4. Davis A, Tinker AV, Friedlander M. “Platinum resistant” ovarian cancer: what is it, who to treat and how to measure benefit? Gynecologic oncology. 2014;133:624-31.
  • 5. Cacan E, Greer SF, Garnett-Benson C. Radiationinduced modulation of immunogenic genes in tumor cells is regulated by both histone deacetylases and DNA methyltransferases. International journal of oncology. 2015;47:2264-75.
  • 6. Thorburn A. Death receptor-induced cell killing. Cellular signalling. 2004;16:139-44.
  • 7. Cacan E, Spring AM, Kumari A, Greer SF, GarnettBenson C. Combination Treatment with Sublethal Ionizing Radiation and the Proteasome Inhibitor, Bortezomib, Enhances Death-Receptor Mediated Apoptosis and Anti-Tumor Immune Attack. International journal of molecular sciences. 2015;16:30405-21.
  • 8. Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22:8628-33.
  • 9. Kykalos S, Mathaiou S, Karayiannakis AJ, Patsouras D, Lambropoulou M, Simopoulos C. Tissue expression of the proteins fas and fas ligand in colorectal cancer and liver metastases. Journal of gastrointestinal cancer. 2012;43:224-8.
  • 10. Yigit R, Massuger LF, Figdor CG, Torensma R. Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecologic oncology. 2010;117:366-72.
  • 11. Zhu Q, Liu JY, Xu HW, Yang CM, Zhang AZ, Cui Y, et al. Mechanism of counterattack of colorectal cancer cell by Fas/Fas ligand system. World journal of gastroenterology : WJG. 2005;11:6125-9.
  • 12. Cacan E. Histone Deacetylase-1-mediated Suppression of FAS in Chemoresistant Ovarian Cancer Cells. Anticancer research. 2016;36:2819- 26.
  • 13. Yang F, Long W, Xuechuan H, Xueqin L, Hongyun M, Yonghui D. Upregulation of Fas in epithelial ovarian cancer reverses the development of resistance to cisplatin. BMB reports. 2015;48:30-5.
  • 14. Schneiderman D, Kim JM, Senterman M, Tsang BK. Sustained suppression of Fas ligand expression in cisplatin-resistant human ovarian surface epithelial cancer cells. Apoptosis : an international journal on programmed cell death. 1999;4:271-81.
  • 15. Di X, Zhang G, Zhang Y, Takeda K, Rivera Rosado LA, Zhang B. Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. Oncotarget. 2013;4:1349- 64.
  • 16. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1-14.
  • 17. Guicciardi ME, Gores GJ. Life and death by death receptors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2009;23:1625-37.
  • 18. Koornstra JJ, Kleibeuker JH, van Geelen CM, Rijcken FE, Hollema H, de Vries EG, et al. Expression of TRAIL (TNF-related apoptosisinducing ligand) and its receptors in normal colonic mucosa, adenomas, and carcinomas. The Journal of pathology. 2003;200:327-35.
  • 19. Driscoll PC. Structural studies of death receptors. Methods in enzymology. 2014;545:201-42.
  • 20. Ozoren N, El-Deiry WS. Cell surface Death Receptor signaling in normal and cancer cells. Seminars in cancer biology. 2003;13:135-47.
  • 21. Djeu JY, Jiang K, Wei S. A view to a kill: signals triggering cytotoxicity. Clinical cancer research : an official journal of the American Association for Cancer Research. 2002;8:636-40.
  • 22. Fox R, Aubert M. Flow cytometric detection of activated caspase-3. Methods in molecular biology. 2008;414:47-56.
  • 23. Coukos G, Tanyi J, Kandalaft LE. Opportunities in immunotherapy of ovarian cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2016;27 Suppl 1:i11-i5.
  • 24. Preston CC, Maurer MJ, Oberg AL, Visscher DW, Kalli KR, Hartmann LC, et al. The ratios of CD8+ T cells to CD4+CD25+ FOXP3+ and FOXP3- T cells correlate with poor clinical outcome in human serous ovarian cancer. PloS one. 2013;8:e80063.
Türk Hijyen ve Deneysel Biyoloji Dergisi-Cover
  • ISSN: 0377-9777
  • Başlangıç: 1938
  • Yayıncı: Türkiye Halk Sağlığı Kurumu
Arşiv
Sayıdaki Diğer Makaleler

Kemoreziztant rahim kanseri hücrelerinin TRAIL ve FAS aracılı apoptoz duyarlılıklarının radyasyon ile arttırılması

Ercan CACAN

Çukurova Üniversitesi Tıp Fakültesi Hastanesi’nde Hepatit C virus genotiplerinin ve HCV enfeksiyonu bulaş yollarının belirlenmesi

Alev Çetin DURAN, Filiz KİBAR, Salih ÇETİNER, Akgün YAMAN

Hitit Üniversitesi Corum Eğitim ve Araştırma Hastanesi’nde Lenfadenopati Ön Tanılı Olguların Toksoplazmoz Açısından İrdelenmesi

A. Semra GÜRESER, Derya YAPAR, Leyla TAŞÇI, Z. İlkay BOYACIOĞLU, Ebru TURGAL, Nurcan BAYKAM, Ayşegül Taylan ÖZKAN