Abstract
Residual androgen receptor (AR)-signaling and presence of cancer stem-like cells (SCs) are the two emerging paradigms for clinically challenging castration-resistant prostate cancer (CRPC). Therefore, identification of AR-target proteins that are also overexpressed in the cancer SC population would be an attractive therapeutic approach.Our analysis of over three hundred clinical samples and patient-derived prostate epithelial cultures (PPECs), revealed Cancerous inhibitor of protein phosphatase 2A (CIP2A) as one such target. CIP2A is significantly overexpressed in both hormone-naïve prostate cancer (HN-PC) and CRPC patients . CIP2A is also overexpressed, by 3- and 30-fold, in HN-PC and CRPC SCs respectively. In vivo binding of the AR to the intronic region of CIP2A and its functionality in the AR-moderate and AR-high expressing LNCaP cell-model systems is also demonstrated. Further, we show that AR positively regulates CIP2A expression, both at the mRNA and protein level. Finally, CIP2A depletion reduced cell viability and colony forming efficiency of AR-independent PPECs as well as AR-responsive LNCaP cells, in which anchorage-independent growth is also impaired.These findings identify CIP2A as a common denominator for AR-signaling and cancer SC functionality, highlighting its potential therapeutic significance in the most clinically challenging prostate pathology: castration-resistant prostate cancer.
Highlights
Since androgen receptor (AR) is instrumental in the progression of prostate cancer (PC) [1], it has been the main focus of therapeutics
The colony forming capacity in the benign prostate hypertrophy (BPH) prostate epithelial cultures (PPECs) was not significantly altered on Cancerous inhibitor of protein phosphatase 2A (CIP2A) depletion (Figure 2D). Together these results indicate that CIP2A is important for the survival of hormonenaïve prostate cancer (HN-PC) stem-like cell (SC) populations
Presence of cancer stem cells adds another layer of complexity for effective treatment, especially in castrationresistant prostate cancer (CRPC) cases [6]
Summary
Since AR is instrumental in the progression of prostate cancer (PC) [1], it has been the main focus of therapeutics. In antiandrogen treated tumors, point mutations abrogating the effect of the drugs have been identified [3] and it has been shown that CRPC cells can produce low levels of androgens endogenously [4]. These adaptations make CRPCs responsive to the second line AR-signaling blocking drugs, such as abiraterone and enzalutamide. The existence of cancer stem cells (SCs) in advanced stage PC and CRPCs has been suggested as another potential mechanism for resistance to drugs [6]. Together these results indicate that efficient therapy for advanced stage PC would require simultaneous targeting of two types of cancer cell populations: those that are dependent on AR-signaling and the AR-independent (cells that are non-responsive to androgens) cancer stem-like cells
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