title: PIM2 kinase is induced by cisplatin in ovarian cancer cells and limits drug efficacy.
abstract: 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.
authors.affiliation: Department of Oncology, University of Torino School of Medicine , 10060 Candiolo (Torino), Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Musiani
authors.forename: Dean E
authors.initials: DE
authors.lastname: Hammond
authors.forename: Luca
authors.initials: L
authors.lastname: Cirillo
authors.forename: Jessica
authors.initials: J
authors.lastname: Erriquez
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clague
authors.forename: Maria Flavia
authors.initials: MF
authors.lastname: Di Renzo
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000379:methods; D051025:bcl-Associated Death Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin
keywords: PIM2 kinase; SILAC phosphoproteomics; ovarian cancer; platinum drugs