PIM2 Kinase Is Induced by Cisplatin in Ovarian Cancer Cells and Limits Drug Efficacy

Platinum-based
chemotherapy is widely used to treat various cancers,
but many patients ultimately relapse due to drug resistance. We employed
phosphoproteomic analysis and functional assays of the response of
SK-OV-3 ovarian cancer cells to cisplatin as a strategy to identify
kinases as candidate druggable targets to sensitize cells to platinum.
A SILAC-based approach combined with TiO2-based phosphopeptide
enrichment allowed the direct identification of ERK1/2, p90RSK, and
ERBB2 as kinases whose phosphorylation is regulated by cisplatin.
Bioinformatic analysis revealed enrichment in linear phosphorylation
motifs predicted to be targets of p38MAPK, CDK2, and PIM2. All three
PIM kinases were found expressed in a panel of 10 ovarian cancer cell
lines, with the oncogenic PIM2 being the most commonly induced by
cisplatin. Targeting PIM2 kinase by either biochemical inhibitors
or RNA interference impaired cell growth, decreased cisplatin-triggered
BAD phosphorylation, and sensitized ovarian cancer cells to drug-induced
apoptosis. Overexpression of PIM2 triggered anchorage-independent
growth and resulted in increased BAD phosphorylation and cell resistance
to DNA damaging agents. The data show that the PIM2 kinase plays a
role in the response of ovarian cancer cells to platinum drugs and
suggest that PIM inhibitors may find clinical application as an adjunct
to platinum-based therapies.