oa Apoptosis resistance in prostate cancer cells and cancer stem cells: Implications of pro- and anti-apoptotic molecules in neuroendocrine differentiation

Prostate cancer (PC) is the second leading cause of cancer related death in men in several countries and is the most common cancer in men in Qatar according to recent statistics of the years 2010 and 2011. Understanding the molecular mechanisms underlying the development of PC progression is critical for developing novel therapies. Neuroendocrine (NE) differentiation of PC cells is an oncogenic process that has been reported as a mechanism contributing to hormone refractory PC progression. NE cells are found in most prostate adenocarcinoma that are significantly enriched as disease progresses, and are extremely resistant to apoptosis caused by androgen ablation therapy, therapeutic drugs or radiation. However, the mechanism of resistance to apoptosis of these cells is not clearly understood resulting in major impediment in PC treatments. The current study aims to initially identify the optimal conditions to induce NE phenotype in PC cells in vitro and to identify the molecules or pathways responsible for resistance to apoptosis in NE cells of prostate adenocarcinoma. Since NE cells are also quiescent as cancer stem cells (CSC), we investigated the relation between NE cells and CSC. Using the expression of NE-specific markers such as Chromogranin A and Neuron specific Enolase (NSE) an optimal method for the differentiation of PC cells to NE cells was identified and used to generate a repertoire of NE-induced PC cells for genome-wide analysis. Our analysis identified differential regulation of pro-apoptotic and anti-apoptotic molecules in NE cells accounting for resistance to apoptosis. We also show that the NE repertoire is highly enriched in CSC as demonstrated by sphere formation method. The identification of key molecules involved in resistance to apoptosis is critical for the development of novel therapeutic drugs that can interfere with NE differentiation and thus PC progression.