Constitutive activation of p70S6k in cancer cells.

The mitogen-stimulated serine/threonine kinase p70S6k plays an important role in the progression of cells from G0/G1 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 p70S6k 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 p70S6k in all cancer cell lines, while wortmannin, a specific inhibitor of PI3-K, caused a mild dephosphorylation of p70S6k in AGS, MDA-MB-435S and MB-157. In addition, SQ20006, methylxanthine phosphodiesterase inhibitor, reduced the phosphorylation of p70S6k in all cancer cells tested. Consistent with inhibitory effect of rapamycin on p70S6k activity, rapamycin inhibited [3H]-thymidine incorporation and increased the number of cells at G0/G1 phase. Furthermore, these inhibitory effects were accompanied by the decrease in growth of cancer cells. Taken together, the results indicate that the antiproliferative activity of rapamycin might be attributed to cell cycle arrest at G0/G1 phase in human cancer cells through the inhibition of constitutively activated p70S6k of cancer cells and suggest p70S6k as a potential target for therapeutic strategies aimed at preventing or inhibiting tumor growth.