Bone metastasis occurs in 80% of lethal androgen independent prostate cancer (PCa) cases, illustrating the need to better understand the mechanisms that regulate PCa growth in the bone. Bone cell paracrine signals affect cancer cell homing and adaption to growth in the bone. One likely means of PCa survival in bone is through the ability of cells to undergo neuroendocrine differentiation (NED). Neuroendocrine differentiated (NE) PCa cells are most prevalent in advanced PCa, correlate with androgen independent disease, and support disease progression. Furthermore, the NE PCa cells can de-differentiate and switch between dormant and proliferative states posing a risk for relapse after treatment. Non-dividing, long-lived NE PCa cells can evade conventional chemo-radiation therapy and contribute to tumor latency, yet remain primed for re-entry into the cell cycle to contribute to tumor growth during recurrence. Bone marrow stromal cell (BMSC) paracrine signaling induces apoptosis in co-cultured bone metastatic PCa cells. However, a subpopulation of the bone metastatic PCa cells can avoid apoptotic cell death and undergo NED. A working model is proposed in which upon arrival to the bone, metastatic PCa cells encounter a hostile microenvironment posed by the innate immune system present there that triggers PCa cell death in the majority of cells. A subpopulation of the PCa cells, however, can activate a molecular program that promotes PCa NED and cell survival in bone. Autophagy - a homeostatic, cell survival process - is up- regulated in PCa cells by BMSCs and helps maintain NE PCa cells in a trans-differentiated state. The molecular mechanisms that direct PCa cell fate either towards apoptosis or towards NED remain unclear. Understanding these mechanisms would provide an opportunity to intervene to prevent cells from undergoing NED and tip the balance toward apoptosis, greatly reducing the odds of relapse. This project aims to demonstrate that BMSCs promote either apoptosis or NED through a common mechanism that involves the repression of androgen receptor (AR) expression, and furthermore, show that autophagy is a cellular rheostat that determines whether a PCa cell undergoes apoptosis or NED following down regulation of AR expression. Using molecular biology tools such as microscopy, western blot, and expression vectors to characterize BMSC-induced PCa apoptosis and NED when AR expression and autophagy are modulated, the following specific aims are proposed:
Specific Aim 1 : Demonstrate that BMSC-mediated AR repression induces PCa apoptosis or PCa NED.
Specific Aim 2 : Determine if autophagy protects PCa cells from apoptosis and directs these cells towards NED in response to BMSC-induced AR repression.
Specific Aim 3 : Dissect the mechanism by which BMSC paracrine signaling represses PCa AR expression.
Metastatic prostate cancer (PCa) is incurable because it is androgen independent and contains neuroendocrine PCa cells. This project will elucidate the role of bone in supporting this aggressive PCa through androgen receptor activity and autophagy and present these regulatory mechanisms as potential therapeutic targets.
| Nawas, Afshan Fathima; Mistry, Ragini; Narayanan, Shrinath et al. (2018) IL-1 induces p62/SQSTM1 and autophagy in ER?+ /PR+ BCa cell lines concomitant with ER? and PR repression, conferring an ER?- /PR- BCa-like phenotype. J Cell Biochem : |
| Thomas-Jardin, Shayna E; Kanchwala, Mohammed S; Jacob, Joan et al. (2018) Identification of an IL-1-induced gene expression pattern in AR+ PCa cells that mimics the molecular phenotype of AR- PCa cells. Prostate 78:595-606 |
