Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasionReport as inadecuate




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Molecular Cancer

, 9:279

First Online: 19 October 2010Received: 04 August 2010Accepted: 19 October 2010

Abstract

BackgroundPim family kinases are small constitutively active serine-threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo2,3-acarbazole-3-carbaldehyde DHPCC-9, which we had recently identified as a potent and selective inhibitor for all Pim family members.

ResultsWe now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases.

ConclusionsAltogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-9-279 contains supplementary material, which is available to authorized users.

Niina M Santio, Riitta L Vahakoski contributed equally to this work.

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Author: Niina M Santio - Riitta L Vahakoski - Eeva-Marja Rainio - Jouko A Sandholm - Sanna S Virtanen - Michelle Prudhomme - Fab

Source: https://link.springer.com/







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