Enhancing Prostate Cancer Sensitivity to TRAIL Anti-tumor Effects by Targeting CXCR4

Prostate cancer is the second most common cancer and the sixth leading cause of cancer death in males worldwide. In Oman, it is the seventh common cancer and the 1st most common cancer diagnosed in males. Many antitumor medications have been developed for prostate cancer but their intolerable systemic toxicity often limits their clinical use. Chemotherapy kills drug-sensitive cells, but leaves a higher proportion of drug-resistant cells which are responsible for chemotherapy failure on tumor recurrence. Cytotoxic drugs kill tumor cells by a variety of mechanisms translated into signals for apoptosis. Despite the relative 5-year survival rate is nearly100%, drug resistance remains a significant obstacle in the control of prostate cancer; with inhibition of apoptosis as one of the mechanisms behind this phenomenon. Selectively killing target tumor cells and sparing normal tissues are among the ultimate goals of cancer research. That is why tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising cancer therapeutic which can specifically kill transformed cells and spare normal cells. There are contradictory data reporting the resistance to apoptosis induced by TRAIL as a single agent in prostate cancer. It was reported that some chemotherapeutic agents can augment TRAIL-induced apoptosis in many cancers types including prostate cancer. Most prostate cancer-related deaths are not the result of primary tumor growth but, rather, are caused by the spread of the cancer to other organs. The CXCL12/CXCR4 axis has been shown to play important roles in prostate tumor cell proliferation, angiogenesis, and metastasis. Amongst the survival-enhancing studies focusing on the CXCL12/CXCR4 axis, its relation to TRAIL-induced effects in prostate cancer is not elucidated. The objective of this proposal is to determine the effects of inhibiting CXCR4 on TRAIL-induced apoptosis in prostate cancer, and to identify the mechanism of such effects. Given the limitations of conventional therapies for prostate cancer, this will be a potentially effective approach to treat prostate cancer and superior to current combination therapies with TRAIL. We hypothesize that down-regulating/inhibiting CXCR4 will enhance the pro-apoptotic effects of TRAIL in prostate cancer and decrease prostate cancer growth and metastasis potential.