Potential for TRAIL as a Therapeutic Agent in Ovarian Cancer

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis, otherwise known as programmed cell death, in many malignant cells without any known detrimental effects to normal cells. These aspects of TRAIL indicate the potential of TRAIL as a therapeutic agent in cancer. Ovarian cancer remains the deadliest gynecologic malignancy and is the fourth leading cause of death due to cancer in women. However, it has been shown in studies that ovarian cancer cells are sensitive to TRAIL-induced cell death when treated with TRAIL alone or in combination with chemotherapeutic agents. TRAIL signals through two death receptors, TRAIL-R1 and TRAIL-R2, to induce apoptosis. TRAIL also binds to two other cell surface receptors, TRAIL-R3 and TRAIL-R4, which do not have intracellular death domains and therefore do not transmit the apoptotic signal upon ligation with TRAIL. It has been shown that a chemokine, interleukin-8 (IL-8), may play a role in ovarian tumor progression due to its elevated presence in the fluid surrounding ovarian cancer tissues. Possible roles for IL-8 in ovarian tumorigenesis include angiogenesis and metastasis. Because the mechanism of regulation for TRAIL-induced apoptosis needs to be clarified, the role of IL-8 in TRAIL-induced apoptosis of ovarian cancer cells was studied. Results showed that the presence of IL-8 regulates cell-surface expression of TRAIL receptors in ovarian cancer cell lines in vitro. There may be a role for the p38 mitogen-activated protein kinase (MAPK) pathway in TRAIL-induced apoptosis of ovarian cancer cell.