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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

BIO-MEDICAL SCIENCES AND ENGINEERING

MS THESIS DEFENSE BY GİZEM HAZAL ŞENTÜRK

 

Title: Characterization of Androgen Receptor Variant Induced Senescence in Prostate Cancer

 

Speaker: Gizem Hazal Şentürk

 

Time: August 9th, 2018, 10:30

 

Place: SNA A52

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

 

Thesis Committee Members:

Assoc. Prof. Dr. Nathan Lack, Advisor (Koç University, Molecular Biology and Genetics)

Assis. Prof. Dr. Tamer Önder (Koç University, Molecular Biology and Genetics)

Assoc. Prof. Dr. Ömer Faruk Bayrak (Yeditepe University, Medical Genetics)

 

Abstract:

Prostate cancer (PCa) is an extremely common disease that affects one out of every seven men and is the second leading cause of cancer-related death. Androgen Receptor (AR) signaling is critical to the cellular proliferation and progression of this disease. With such an essential role, inhibition of the AR via Androgen deprivation therapy (ADT) is one of the primary treatments for PCa patients who have failed surgery or radiotherapy. While ADT is initially effective, the cancer eventually develop resistance. At this stage the growth of the cancer occurs independent of androgen and it is defined as Castration resistant prostate cancer (CRPC). Several different mechanisms can cause CRPC including AR splice variants. These constitutively active variants do not require androgen to initiate transcription and have been observed in both metastatic human PCa cell lines and xenografts. ARV7 is the most commonly observed AR variant in CRPC patient samples. Demonstrating this importance, patients who express ARV7 are much more likely to develop resistance to antiandrogens.

Our laboratory recently demonstrated that ARV7 expression induces cellular senescence. Yet given the clinical importance of this variant in CRPC this suggests that PCa cells must develop resistance to this oncogene. Therefore, the aim of this study was to characterize the mechanism underlying Variant Induced Senescence (VIS) and try to understand how cells develop resistance. AR-FL regulates the expression of Skp2 an E3 ubiquitin ligase that targets p27. Based on our earlier work we proposed that ARV7 may induce senescence through p27 in relation with Skp2 regulation. Therefore, we characterized the senescence phenotype of both senescence sensitive and resistant cell lines through up-regulation and down-regulation of those tumor suppressor genes. Our results show that, p27 is important for ARV7 induced senescence, which is abundant in senescence sensitive clone and degraded in senescence resistant clones. Despite the altered level of the Skp2 as a regulator of p27 through ubiquitin-mediated proteasome pathway, we showed by the down-regulation of Skp2 it is not the main regulator p27 in the ARV7 induced senescence sensitivity or resistance development mechanism. In addition, to investigate if there is a relation between chromosomal arrangement or neuroendocrine differentiation with the resistance phenotype, we performed karyotype analysis as well as the analysis of the neuroendocrine prostate cancer markers in senesence sensitive and resistance clones. We conclude that, there is no significant modification in the chromosome structure of the resistant clones when compared to sensitive clone. The neuroendocrine differentiation markers does not induce the resistant phenotype in the clones that bypasses arrest despite the ARV7 expression.

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