PIM kinase isoform specific regulation of MIG6 expression and EGFR signaling in prostate cancer cells

Allan Siu 1 , Carl Virtanen 2 and Jan Jongstra 1 1 Genetics and Development Division, Toronto Western Research Institute, University Health Network, Toronto, Canada and Department of Immunology, University of Toronto, Toronto, Canada 2 Microarray Centre, University Health Network, Toronto, Canada. Received: December 17, 2011; Accepted: December 20, 2011; Published: December 21, 2011; Keywords: M-110, PIM-1, MIG6, EGFR, Gefitinib, prostate cancer Correspondence: Jan Jongstra, email: // // Abstract The PIM family of oncogenic serine/threonine kinases regulates tumour cell proliferation. To identify proliferative signaling pathways that are regulated by PIM kinases we analyzed gene expression differences in DU-145 and PC3 prostate cancer derived cells induced by treatment with the recently developed highly selective PIM kinase inhibitor M-110. This identified 97 genes the expression of which is affected by M-110 in both cell lines. We then focused on the M-110 induced up regulation of the MIG6 gene that encodes a negative regulator of EGFR signaling.  Here we show that M-110 and the structurally unrelated PIM kinase inhibitor SGI-1776 up regulate MIG6 in DU-145 and PC3 cells.  Knockdown of PIM-1 but not of PIM-2 or PIM-3 also up regulates MIG6 expression, which identifies MIG6 as a PIM-1 regulated gene.  In agreement with the role of MIG6 protein as a negative regulator of EGFR signaling we found that M-110 treatment inhibits EGF induced EGFR activation and the activation of the downstream ERK MAPkinase pathway. The biological significance of these findings are demonstrated by the fact that  co-treatment of DU-145 or PC3 cells with the EGFR tyrosine kinase inhibitor Gefitinib and M-110 or SGI-1776 has synergistic  inhibitory effects on cell proliferation.  These experiments define a novel biological function of PIM-1 as a co-regulator of EGFR signaling and suggest that PIM inhibitors may be used in combination therapies to increase the efficacy of EGFR tyrosine kinase inhibitors.