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Background:The interaction of PAK1 and the RAF-MEK-ERK cascade is unclear. Results: Overexpression of a kinase-dead mutant form of PAK1 increased phosphorylation of MEK1/2 and ERK. Hyperactivated Rac1 induced the formation of a triple complex of Rac1, PAK1, and MEK1 independent of the kinase activity of PAK1. Conclusion: PAK1 activated MEK-ERK cascade in a kinase-independent manner. Significance: PAK1 might be a scaffold to facilitate interaction of C-RAF and MEK1.

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SUMMARYMetformin and vitamin D 3 both exhibit a strong antiproliferative action in numerous cancer cell lines, including in human prostate cancer cells. Here we showed that the combination of the two drugs had a much stronger effect on DU145 human prostate cancer cell growth than either drug alone. In this research, cell proliferation was measured by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was determined with Hoechst 33342 staining. Western blotting and cell cycle analyses were used to elucidate potential mechanisms of interaction between the drugs. It is shown that in cultured DU145 cells, vitamin D 3 combined with metformin exhibits synergistic effects on cell proliferation and apoptosis. The underlying antitumor mechanisms may involve altered cycle distribution with a G1/S cell cycle arrest, activation of phospho-AMPK with subsequent inhibition of downstream mTOR signalling pathway, down-regulate c-Myc expression, and reducing the level of anti-apoptotic protein p-Bcl-2. In conclusion, metformin and vitamin D 3 synergistically inhibit DU145 cell growth, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.