Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes

Mumenthaler, Shannon M.; Ng, Patricia Y.B.; Hodge, Amanda; Bearss, David J.; Berk, Gregory; Kanekal, Sarath; Redkar, Sanjeev; Taverna, Pietro; Agus, David B.; Jain, Anjali

doi:10.1158/1535-7163.mct-09-0293

Cited by 115 publications

(123 citation statements)

References 45 publications

(63 reference statements)

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“…Inhibiting Pim-1 also has the potential advantage of inhibiting drug resistance mediated by both Pgp and BCRP. It is noteworthy that our data on SGI-1776 resensitization of Pgp-overexpressing cells to a Pgp substrate drug are consistent with recently published data demonstrating SGI-1776 resensitization of 22Rv1 prostate cancer cells to paclitaxel (Mumenthaler et al, 2009). Both that study and ours focused on cancer cells, and it is not yet known whether Pim-1 inhibition also affects Pgp levels in nonmalignant cells, such as CD56 ϩ lymphocytes.…”

Section: Discussionsupporting

confidence: 92%

“…Pim-1 kinase was inhibited by incubation with the Pim-1-selective kinase inhibitor SGI-1776 (Chen et al, 2009, Mumenthaler et al, 2009, generously provided by SuperGen, Inc. (Dublin, CA). SGI-1776 was used at 1 M in 0.1% DMSO because it inhibits Pim-1 at a concentration of 7 ϩ 1.8 nM and is selective for Pim-1, Pim-2, Pim-3, FLT3, and haspin in this concentration range but is more than 95% bound to human plasma…”

Section: Methodsmentioning

confidence: 99%

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Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

et al. 2010

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The oncogenic serine/threonine kinase Pim-1 phosphorylates and activates the ATP-binding cassette transporter breast cancer resistance protein (ABCG2). The ABC transporter P-glycoprotein (Pgp; ABCB1) also contains a Pim-1 phosphorylation consensus sequence, and we hypothesized that Pim-1 also regulates Pgp. Pgp is exported from the endoplasmic reticulum (ER) as a 150-kDa species that is glycosylated to 170-kDa Pgp, translocates to the cell surface, and mediates drug efflux; alternatively, 150-kDa Pgp is cleaved to a 130-kDa proteolytic product by ER proteases or undergoes ubiquitination and proteasomal degradation. Pim-1 and Pgp interaction was studied in GST pull-down and phosphorylation in in vitro kinase assays. Pim-1 knockdown and inhibition effects on Pgp expression were studied by immunoblotting and flow cytometry and on Pgp stability by immunoblotting after cycloheximide treatment. Pim-1 directly interacted with and phosphorylated Pgp in intact cells and in vitro. Pim-1 knockdown or inhibition decreased cellular and cell surface 170-kDa Pgp, in association with both transient increase in 130-kDa Pgp and increased Pgp ubiquitination and proteasomal degradation. Pim-1 inhibition also decreased expression of 150-kDa Pgp in the presence of the glycosylation inhibitor 2-deoxy-D-glucose. Finally, Pim-1 inhibition sensitized Pgp-overexpressing cells to doxorubicin. Thus, Pim-1 regulates Pgp expression by protecting 150-kDa Pgp from proteolytic and proteasomal degradation and enabling Pgp glycosylation and cell surface translocation and thus Pgpmediated drug efflux. Pim-1 inhibitors are entering clinical trials and may provide a novel approach to abrogating drug resistance.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

et al. 2010

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“…123 The most recent studies demonstrated that SGI-1776 induced apoptosis in chronic lymphocytic leukemia (CLL) cells as well as in prostate cancer cell lines. 124,125 Encouraging experimental results initiated clinical trials to explore the haematologica | 2010; 95(6) safety of SGI-1776 for the treatment of refractory nonHodgkin's lymphoma and prostate cancer patients (ClinicalTrials.gov Identifier: NCT00848601).…”

Section: -121mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

425

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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“…Recently, a selective small-molecule PIM inhibitor, SGI-1776, was identified and shown to inhibit the survival of leukemia cells and the proliferation of prostate cancer cell lines (30). Here, we describe compound M-110, a novel and highly selective inhibitor of PIM kinases with a preference for PIM-3.…”

Section: Introductionmentioning

confidence: 95%

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

Chang

Kanwar

Feng

et al. 2010

Molecular Cancer Therapeutics

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Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC 50 s of 0.6 to 0.9 μmol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 μmol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3 , we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3 Tyr705. The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3 Tyr705 . These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3 Tyr705

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Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes

Abstract: The serine/threonine

Cited by 115 publications

References 45 publications

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

Pim-1 Kinase Protects P-Glycoprotein from Degradation and Enables Its Glycosylation and Cell Surface Expression

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

PIM Kinase Inhibitors Downregulate STAT3Tyr705 Phosphorylation

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