Regulation of autophagy by transforming growth factor-β (TGFβ) signaling

Transforming growth factor-beta (TGF beta) has broad impacts on an array of diverse cellular functions including cell growth, differentiation, adhesion, migration and apoptosis. Perturbations of the TGF beta signaling pathways are involved in progression of various tumors. Autophagy is a pivotal response of normal and cancer cells to environmental stresses and is induced by various stimuli. Otherwise, autophagy has an intrinsic function in tumor suppression. Recently, we demonstrated that TGF beta induces autophagy in hepatocellular carcinoma cells and mammary carcinoma cells. Autophagy activation by TGF beta is mediated through the Smad and JNK pathways. We show that siRNA-mediated knockdown of autophagy genes suppresses the growth inhibitory function of TGF beta and that autophagy activation potentiates TGF beta-mediated induction of proapoptotic genes, Bim and Bmf, in hepatoma cells. In this context, the autophagy pathway might contribute to the growth inhibitory effect of TGF beta, in conjunction with other antiproliferative pathways downstream of TGF beta signaling. The context and manner by which the TGF beta signaling pathway regulates autophagy have implications for a better understanding of pathological and bidirectional roles of TGF beta signaling pathways in tumorigenesis.