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

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-dihydropyrrolo[2,3-a]carbazole-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.

Clinical and therapeutic relevance of PIM1 kinase in gastric cancer

“…Loss of nuclear expression and gain of cytoplasmic expression appear to be the likely mechanisms of oncogenesis in gastric cancers, although further work will be needed to verify this hypothesis. Our finding that cytoplasmic PIM1 expression correlates inversely with the presence of lymphovascular invasion is potentially interesting in view of a recent report that implicates PIM1 in invasion and metastasis [33]. The identification of high-level PIM1 genomic amplification by aCGH suggests that overexpression and subsequent gain of PIM1 function might occur in a subset of gastric cancers.…”

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

“…Interestingly, while PIM1 did not alter BAD phosphorylation levels, both PIM2 and PIM3 reduced BAD phosphorylation and total BAD levels after PIM2 knockdown (Fig. 9D), which might explain the proapoptotic effects seen after knockdown of PIM2 and PIM3 (32,(46)(47)(48). Taken together, the proapoptotic effects of PIM inhibitors and their effect on CXCR4 downregulation from the cell surface are mediated by different PIM kinases, with PIM1 regulating the CXCR4 surface expression and PIM2/PIM3 supporting survival of CLL cells.…”

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

“…Among other activities, PIM1 and PIM3 act by repressing apoptosis 30,39,40 and by stimulating the invasion activity of cancer cells. 41 These characteristics are reflected in the gene silencing experiments shown here, where downregulation of PIM1 and PIM3 expression determines cell death and a decrease of invasiveness. In particular, as far as GBM cells are concerned, PIM3 seems to be more relevant than PIM1.…”