Prostate cancer (PC) is curable at an early stage but in late stages it is life-threatening as hormonal ablation is not curative. At an early stage, androgen ablation leads to the death of PC cells that are androgen-dependent. However, PC progression leads to the development of castration-resistant prostate cancer (CRPC) where PC cells no longer depend on androgens for survival and growth. CRPC remains incurable. During progression, metastasis of PC cells is triggered by the attenuation of cell-cell contact dependent communication, which is mediated by cell-cell adhesion molecules that often assemble into cell junctions such as adherens junctions and tight junctions. Cell junctions are essential for maintaining the polarized state of epithelial cells in many tissues and their loss facilitates metastasis. Adherens junctions are formed of cadherins (Cads), which belong to a large family of proteins. Of all the Cads, the role of E-Cad and N-Cad, which are expressed in the epithelial cells and the mesenchymal and neuronal cells, respectively, is well-studied. We will explore the role of cadherin-catenin complex in activating Hippo pathway regulator YAP1 and governing PC progression to CRPC. We have found that YAP1 regulates PC cell motility, invasion, and CRPC cell growth. In androgen-dependent PC cells, YAP1 levels are low and it is localized in the cytoplasm whereas in androgen-independent cells YAP1 levels are high and it is localized in the nucleus. We have found that the inducible expression of ?-catenin (Cat) in ?-Cat null PC cells inhibits growth and decreases YAP accumulation in the nucleus with concomitant increase in the cytosol and cell-cell contact areas. Our central hypothesis is that cadherin-catenin complex suppresses PC progression and triggers CRPC by both cell-cell contact dependent and independent mechanisms by regulating YAP1 level and activation.
The aim of our studies is to investigate how ?-Cat regulates androgen-dependent and CRPC cell growth.in vitro. The hypothesis to be tested is that ?-Cat inhibits YAP activation to suppress androgen receptor-mediated signaling. We will conditionally knock-down and knocked-in ?-Cat in androgen-dependent and -independent PC cell lines, respectively. Progression to androgen-independence will be assessed by measuring cell growth and the levels of androgen-regulated genes, such as prostate-specific antigen, NKX3.1, PGC-1, and KLK2, in the presence and absence of androgens. If cadherin-catenin complex mediated loss of cell junctions and cell-cell adhesion turns out to be causally linked to the emergence of CRPC cells via modulation of YAP activity, restoring junction formation by pharmacological and antineoplastic agents and inhibiting signaling pathways that disrupt cell junctions will revert CRPC to androgen-dependent state and augment the therapeutic effects of androgen ablation.
Prostate cancer is one of the leading causes of cancer-related deaths. Androgen-deprivation therapy delays prostate cancer progression and survival, but eventually fails. There is a dire need to identify new pathways to target refractory patients. Understanding how loss of cell-cell adhesion facilitates development of castration-resistant prostate cancer will open innovative avenues for designing new therapeutic approaches.
