Constitutive activation of p70(S6k) in cancer cells

Abstract

The mitogen-stimulated serine/threonine kinase p70(s6k) plays an important role in the progression of cells from G(0)/G(1) to S phase of the cell cycle by translational up-regulation of a family of mRNA transcripts family of mRNA transcripts which contain polypyrimidine tract at their 5 transcriptional start site. Here, we report that p70(S6k) was constitutively phosphorylated and activated to various degrees in serum-deprived AGS, A2058, HT-1376, MG63, MCF7, MDA-MB-435S, MDA-MB-231 and MB-157. Rapamycin treatment induced a significant dephosphorylation and inactivation of p70(S6k) in all cancer cell lines, while wortmannin, a specific inhibitor of P13-K, caused a mild dephosphorylation of p70(s6k) in AGS, MDA-MB-435S and MB-157. In addition, SQ20006, methylxanthine phosphodiesterase inhibitor, reduced the phosphorylation of p70(S6k) in all cancer cells tested. Consistent with inhibitory effect of rapamycin on p70(S6k) activity, rapamycin inhibited [H-3]-thymidine incorporation and increased the number of cells at G(0)/G(1) phase. Furthermore, these inhibitory effects were accompanied by the decrease in growth of cancer cells. Taken together, the results indicate that the anti proliferative activity of rapamycin might be attributed to cell cycle arrest at G(0)/G(1) phase in human cancer cells through the inhibit