Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70(s6K) pathway in human pancreatic cancer cells

The FRAP-p70(s6K) signaling pathway was found to be constitutively phosphor ylated/active in MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a p ancreatic cancer tissue sample as judged by the retarded electrophoretic mo bility of the two major FRAP downstream targets, p70(s6K) and 4E-BP1, Treat ment of cells with rapamycin, a selective FRAP inhibitor, inhibited basal p 70(s6K) kinase activity and induced dephosphorylation of p70(s6K) and 4E-BP 1, Moreover, rapamycin inhibited DNA synthesis as well as anchorage-depende nt and -independent proliferation in MiaPaCa-2 and Panc-1 cells. Finally, r apamycin strikingly inhibited cyclin D1 expression in pancreatic cancer cel ls. Thus, inhibitors of the constitutively active FRAP-p70(s6K) pathway may provide a novel therapeutic approach for pancreatic cancer.