One long-standing dogma of anticancer therapies has been that such treatments selectively target rapidly-dividing cells. However, this rationale is not satisfactory, as some curable cancers may grow relatively slowly and many rapidly dividing cancer cells are resistant to antineoplastic therapies. In recent years, the molecular mechanisms regulating apoptosis have been investigated, and evidence has emerged indicating that perturbation of the signaling cascades regulating apoptosis, as a result of tumor development, regulates the sensitivity of cancer cells to pro-apoptotic treatments. Therefore, defining and manipulating the apoptotic thresholds of neoplastic cells will further our understanding of the etiology and pathogenesis of human cancer and accordingly permit the development of more efficient treatments. We have demonstrated that Ras, as a signal transducer, regulates two distinct and opposite biological processes: cell proliferation and apoptosis. Under normal growth conditions, Ras transmits mitogenic signals to promote cell differentiation/proliferation. Under the conditions in which endogenous PKC is suppressed, the same Ras is re-directed to participate in the apoptotic process. We also demonstrated that Ras recruits signals from various apoptotic pathways. Bcl-2 protects cells against Ras-mediated cell death. In this proposal, we design a number of critical experiments to study the mechanisms of Ras- mediated apoptosis. For example, using antisense oligo technique or siRNA system, we will determine which PKC isoforms are involved in this process. Employing ras mutants that preferentially activate one of Ras pathways, we are able to dissect Ras signaling and identify the downstream apoptotic effectors. Also, using various bcl-2 mutants, we are able to determine how Bcl-2 interferes with Ras-mediated apoptosis. Our studies, using molecular and cellular techniques, will be directed at three specific aims: (1) to determine the signals in the regulation of Ras-mediated apoptosis; (2) to define the downstream effectors of Ras which mediate the apoptotic process; and (3) to determine the anti-apoptotic function of Bcl-2 in Ras-initiated apoptosis. Overall, the experiments will help us to further understand how Ras-mediated apoptosis is regulated. Such understanding is aimed to translate into new strategy for cancer therapy targeting tumors containing oncogenic ras.
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