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

Abstract

Transforming growth factor-β (TGFβ) has broad impacts on an array of diverse cellular functions including cell growth, differentiation, adhesion, migration and apoptosis. Perturbations of the TGFβ 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 TGFβ induces autophagy in hepatocellular carcinoma cells and mammary carcinoma cells. Autophagy activation by TGFβ is mediated through the Smad and JNK pathways. We show that siRNA-mediated knockdown of autophagy genes suppresses the growth inhibitory function of TGFβ and that autophagy activation potentiates TGFβ-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 TGFβ, in conjunction with other antiproliferative pathways downstream of TGFβ signaling. The context and manner by which the TGFβ signaling pathway regulates autophagy have implications for a better understanding of pathological and bidirectional roles of TGFβ signaling pathways in tumorigenesis. © 2010 Landes Bioscience.