Journal
ONCOGENE
Volume 29, Issue 21, Pages 3100-3109Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.63
Keywords
PKC epsilon; Stat3; human cancer
Funding
- DOD [W81XWH]
- NIH [CA35368]
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Protein kinase C epsilon (PKC epsilon), a novel calcium-independent PKC isoform, has been shown to be a transforming oncogene. PKC epsilon-mediated oncogenic activity is linked to its ability to promote cell survival. However, the mechanisms by which PKC epsilon signals cell survival remain elusive. We found that signal transducers and activators of transcription 3 (Stat3), which is constitutively activated in a wide variety of human cancers, is a protein partner of PKC epsilon. Stat3 has two conserved amino-acid (Tyr705 and Ser727) residues, which are phosphorylated during Stat3 activation. PKC epsilon interacts with Stat3 alpha isoform, which has Ser727, and not with Stat3 beta isoform, which lacks Ser727. PKC epsilon-Stat3 interaction and Stat3-Ser727 phosphorylation was initially observed during induction of squamous cell carcinomas and in prostate cancer. Now we present that (1) PKC epsilon physically interacts with Stat3 alpha isoform in various human cancer cells: skin melanomas (MeWo and WM266-4), gliomas (T98G and MO59K), bladder (RT-4 and UM-UC-3), colon (Caco-2), lung (H1650), pancreatic (PANC-1), and breast (MCF-7 and MDA: MB-231); (2) inhibition of PKC epsilon expression using specific siRNA inhibits Stat3Ser727 phosphorylation, Stat3-DNA binding, Stat3-regulated gene expression as well as cell invasion; and (3) PKC epsilon mediates Stat3Ser727 phosphorylation through integration with the MAPK cascade (RAF-1, MEK1/2, and ERK1/2). The results indicate that PKC epsilon-mediated Stat3Ser727 phosphorylation is essential for constitutive activation of Stat3 and cell invasion in various human cancers. Oncogene (2010) 29, 3100-3109; doi: 10.1038/onc.2010.63; published online 15 March 2010
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