Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis

Protein kinase C epsilon (PKC epsilon) has emerged as an oncogenic protein kinase and plays important roles in cancer cell survival, proliferation, and invasion. It is, however, still unknown whether PKC epsilon affects cell proliferation via glucose metabolism in cancer cells. Here we report a novel function of PKC epsilon that provides growth advantages for cancer cells by enhancing tumor cells glycolysis. We found that either PKC epsilon or Smad2/3 promoted aerobic glycolysis, expression of the glycolytic genes encoding HIF-1, HKII, PFKP and MCT4, and tumor cell proliferation, while overexpression of PKC epsilon or Smad3 enhanced aerobic glycolysis and cell proliferation in a protein kinase D- or TGF--independent manner in PC-3M and DU145 prostate cancer cells. The effects of PKC epsilon silencing were reversed by ectopic expression of Smad3. PKC epsilon or Smad3 ectopic expression-induced increase in cell growth was antagonized by inhibition of lactate transportation. Furthermore, interaction of endogenous PKC epsilon with Smad2/3 was primarily responsible for phosphorylation of Ser213 in the Samd3 linker region, and resulted in Smad3 binding to the promoter of the glycolytic genes, thereby promoting cell proliferation. Forced expression of mutant Smad3 (S213A) attenuated PKC epsilon-stimulated protein overexpression of the glycolytic genes. Thus, our results demonstrate a novel PKC epsilon function that promotes cell growth in prostate cancer cells by increasing aerobic glycolysis through crosstalk between PKC epsilon and Smad2/3.