TRAIL is a membrane protein that can be released from cells and which induces a specific form of cell death, termed “apoptosis” in sensitive cells. Since the majority of currently available anti-cancer drugs kill target cells by inducing apoptosis, the ability of TRAIL to induce apoptosis suggests it might prove useful as a cancer therapeutic agent. TRAIL induces apoptosis in cells derived from human lung, breast, colon, kidney, brain, prostate and skin cancers in vitro and also induces apoptosis of tumor cells, stops tumor progression and improves survival in animal models. These studies suggest that TRAIL has significant potential as a novel agent for the treatment of a variety of human cancers. The potential of TRAIL as an agent for cancer therapy is limited, however, because cancer cells of all types differ in sensitivity to TRAIL-induced apoptosis and some human cancer cells, including cells derived from human ovarian cancers, are resistant to TRAIL-induced apoptosis. But infecting a cell with reovirus sensitizes some human cancer cells, including ovarian cancer cells, to TRAIL-induced apoptosis. This project will identify the molecular mechanisms by which viral infection makes cells sensitive to TRAIL. Results could provide ways in which TRAIL could be used in treatment for ovarian and other cancers.
This award has been made possible by a generous grant from The Patricia A. Brown Charitable Lead Annuity Trust.
Dr. Clarke’s interests include viral-induced apoptosis and signaling pathways. She has demonstrated that reovirus-induced regulation of the transcription factor nuclear factor kappa B (NF-kB) is required for the apoptotic cell death of virus-infected cells. Reovirus-induced apoptosis thus requires both an early phase of activation and a later phase where the activation of NF-kB is blocked. Dr. Clarke has also shown that activation of both c-Jun N-terminal kinase (JNK) and that c-Jun transcription factor are also associated with reovirus-induced cell death. In addition, work performed by Dr. Clarke has demonstrated that reovirus-induced apoptosis is mediated by TNF-related apoptosis inducing ligand (TRAIL), which binds to cell surface death receptors DR4 and DR5 resulting in the FADD-dependent activation of cellular caspases. Finally, Dr. Clarke has shown that reovirus can sensitize cells, including cell lines derived from a variety of human cancers, to TRAIL-induced apoptosis by a mechanism that involves an increase in the activation of caspase 8.