The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth

Cancer cells can remodel surrounding microenvironments to facilitate cell growth, invasion, and migration by secreting proteins that educate surrounding stromal cells. We report that p85(S6K1), the longest isoform of S6K (ribosomal protein S6 kinase), but not the shorter isoform p70(S6K1) or p56(S6K2), was secreted from cancer cells through its HIV TAT-like, N-terminal six-arginine motif. The exogenously produced p85(S6K1) protein entered cultured transformed and nontransformed cells to promote or confer malignant behaviors, leading to increased cell growth and migration. When injected into mice, the p85(S6K1) protein enhanced the growth of xenografted breast cancer cells and lung metastasis. Hence, our findings reveal a role for p85(S6K1) as a secreted oncogenic kinase and provide a mechanism by which cancer cells remodel their microenvironment by transforming the surrounding cells to drive tumorigenesis.