![]() ![]() This synergistic effect was mediated by CHOP and JNK, proapoptotic factors associated with chronic ER stress. We confirmed that pretreatment with taxanes significantly enhanced the susceptibility of DU145 and PC3 cells to TRAIL-induced apoptosis compared with taxane or TRAIL alone. In this study, we investigated the role of ER stress in the mechanism of sensitization of prostate cancer cells to TRAIL-induced apoptosis via taxane pretreatment, and we adopted a computational model to predict this synergistic effect of apoptosis in each cell line. Although there have been numerous studies that have examined TRAIL sensitization in prostate cancer cells with clinically-relevant chemotherapies, these studies do not fully explore the role of ER stress in the mechanism behind TRAIL sensitization using these taxanes ( 37–41). Previous studies have shown the sensitization of prostate cancer cells to TRAIL-induced apoptosis when treated with different small molecules ( 27–36). Like stem cells, CSCs constitute a small subpopulation in tumors that have clonogenic and self-renewal abilities that can help explain their tumorigenicity, metastatic potential, and chemotherapy/radiotherapy resistance ( 8–11). In the last decade, there has been more attention and focus on cancer stem cells (CSC) and their role in tumor recurrence and poorer prognosis in patients with mCRPC. Effective treatment options for patients with mCRPC still remain a significant clinical problem because resistance to chemotherapy treatment and metastatic progression still occur. Cabazitaxel (CBZ), the dimethoxy derivative of docetaxel, becomes the second line of treatment demonstrating a survival benefit for patients with docetaxel-refractory mCRPC ( 6, 7). Unfortunately, most patients develop resistance to docetaxel. Docetaxel is the first line of treatment given to patients with mCRPC who stop responding to conventional therapies ( 4–6). ![]() FDA-approved chemotherapies for mCRPC are taxanes, docetaxel (DTX) and cabazitaxel. Once prostate cancer has reached an advanced stage that no longer responds to hormone treatment or chemotherapy, a situation called metastatic castration-resistant prostate cancer (mCRPC), treatment options are limited ( 3). Prostate cancer is the second leading cause of death in U.S. Pretreatment with taxanes sensitized cells to apoptosis induced by TRAIL-mediated apoptosis, demonstrating that combining TRAIL with ER stress inducers is a promising therapy to reverse TRAIL resistance to treat mCRPC. A computational model was used to simulate apoptosis for cells treated with taxane and TRAIL therapy as demonstrated in in vitro experiments. Cytochrome c knockdown showed a significant decrease in sensitivity in PC3 cells, but not in Bax-deficient DU145 cells. In addition, suppression of C/EBP homologous protein (CHOP) reduced TRAIL sensitization in both cell lines indicating that ER stress–related apoptosis is mediated, in part, by CHOP. A Jun N-terminal kinases (JNK) inhibitor inhibited apoptosis in treated cells and significantly reduced death receptor expression indicating JNK activation by ER stress sensitizes PCa cells to TRAIL-induced apoptosis by upregulating DR4/DR5 expression. Taxane and TRAIL combination synergistically amplified apoptosis strongly suggesting that taxanes sensitize prostate cancer cells to TRAIL. DU145 and PC3 cells displayed no significant reduction in cell viability when treated with soluble TRAIL, docetaxel, or cabazitaxel alone indicating that both cell lines are resistant to TRAIL and taxanes individually. In this study, we sensitized androgen-independent and TRAIL-resistant prostate cancer cells to TRAIL-mediated apoptosis via taxane therapy and examined the mechanism of sensitization. TNF-related apoptosis inducing ligand (TRAIL) is an anticancer agent that is selectively cytotoxic to cancer cells however, many human cancers are resistant to TRAIL. Docetaxel and cabazitaxel are guideline-chemotherapy treatments for metastatic castration-resistant prostate cancer (mCRPC), which comprises the majority of prostate cancer deaths. ![]()
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