MECHANISMS OF TGE-B RESISTANCE IN COLON CARCINOMA CELLS

点击翻译按钮获取中文摘要

TGF-beta may potentially be successful in the treatment of colon cancer since it inhibits the proliferation of responsive human colon carcinoma cells and elicits differentiation-like effects. However, approximately 50% of colon carcinoma cells tested were unresponsive to TGF-beta. The overall goal of this proposal is to expand a previously-established model system for TGF-beta resistance in human colon carcinoma cells, and to utilize this model system to identify possible mechanisms underlying TGF-beta resistance. The result obtained from this proposal will identify targets for the development of drugs which will either mimic the inhibitory effects of TGF-beta on epithelial colon tumors or which will eliminate the development of resistance to growth regulation by TGF-beta. Areas of investigation aimed at elucidating mechanisms of action of and/or of resistance to TGF-beta include: (1) Characterization of receptor binding and receptor subtypes in the resistant and sensitive clones, (2) Investigation of the involvement or alteration of G proteins and of ras oncoproteins in transduction of cellular signals generated by TGF-beta (G proteins appear to be involved in TGF-beta-induced mitogenesis in fibroblast cells), and (3) Investigation of alterations in the regulation of expression of the nuclear proto-oncogenes c-myc, c-fos, and c-jun (and their protein products) to identify any alterations in these molecular links between signal transduction and transcriptional regulation. Previous work indicated that 3/4 of initially-identified TGF-Beta-resistant clones over-expressed c-myc, an event which has been shown to alter TGF-Beta responsiveness in other cells. Additional experiments will be focused on the cellular environment as a mediator of altered TGF-beta responsiveness. Overproduction of, or responsiveness to, growth stimulatory autocrine factors in the resistant clones may outweigh any potential inhibitory effects of TGF-beta. Therefore, involvement of EGF, TGF-alpha and the EGF receptor in TGF-beta resistance will be addressed.