Protein Kinase C  Represses the Interleukin-6 Promoter and Impairs Tumorigenesis In Vivo

Gene alterations in tumor cells that confer the ability to grow under nutrient- and mitogen-deficient conditions constitute a competitive advantage that leads to more-aggressive forms of cancer. The atypical protein kinase C (PKC) isoform, PKC zeta, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKC zeta-deficient mice display increased Ras-induced lung carcinogenesis, suggesting a new role for this kinase as a tumor suppressor in vivo. We also show that Ras-transformed PKC zeta-deficient lungs and embryo fibroblasts produced more interleukin-6 (IL-6), which we demonstrate here plays an essential role in the ability of Ras-transformed cells to grow under nutrient- deprived conditions in vitro and in a mouse xenograft system in vivo. We also show that PKC zeta represses histone acetylation at the C/EBP beta element in the IL-6 promoter. Therefore, PKC zeta, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.