Transforming Growth Factor-β1 Inhibits Membrane Association of Protein Kinase Cα in a Human Prostate Cancer Cell Line, PC3.

The postreceptor signaling pathway(s) that mediates the effects of transforming growth factor-b1 (TGF-b1) is incompletely understood. The present study investigated the involvement of protein kinase C (PKC) in the growth-inhibitory action of TGF-b1 in PC3, a human prostate cancer cell line. PKCa, the only conventional PKC isoform detected in PC3 cells, appeared to be constitutively active based on its presence in both Triton-soluble membrane fraction and cytosol. However, levels of membrane-associated PKCa were decreased by a growth-inhibitory dose of TGF-b1. The response to TGF-b1 was rapid (within 5 min), time dependent, isoform specific, and occurred without apparent changes in levels of total PKCa protein. TGF-b1 also decreased the levels of membrane-associated PKC activity coincident with its inhibitory effect on PKCa’s membrane association. Inhibition of PKC activity appeared to be associated with growth inhibition in PC3 cells, because chelerythrine (a specific PKC inhibitor) likewise decreased cell proliferation. Taken together, our data suggest that inhibition of PKC activity, at least in part due to inactivation of PKCa, is an early event associated with TGF-b1 postreceptor signaling that might mediate suppression of cell proliferation. (Endocrinology 138: 4657–4664, 1997) T growth factor-b (TGF-b) is a multifunctional regulator of cellular growth and differentiation (1, 2). It is capable of stimulating or inhibiting these processes depending on cell type and the extracellular milieu or culture conditions. In a variety of normal and transformed cells, particularly those of epithelial, endothelial, and hematopoetic origin, TGF-b is a potent inhibitor of cell proliferation (1, 2). However, cells often escape the growth inhibitory influence of TGF-b, and this condition may lead to uncontrolled growth or malignancies (3). A full understanding of TGF-b signaling is indeed critical to normal and tumor cell