Oncotarget

Research Papers:

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

Allan Siu, Carl Virtanen, Jan Jongstra _

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Oncotarget. 2011; 2:1134-1144. https://doi.org/10.18632/oncotarget.386

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Abstract

Allan Siu1, Carl Virtanen2 and Jan Jongstra1

1Genetics and Development Division, Toronto Western Research Institute, University Health Network, Toronto, Canada and Department of Immunology, University of Toronto, Toronto, Canada

2Microarray 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.


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