Pim2 is important for regulating DNA damage response in multiple myeloma cells

Ramachandran, Janani; Santo, Loredana; Siu, Ka Tat; Panaroni, Cristina; Raje, Noopur

doi:10.1038/bcj.2016.73

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…In tumor entities other than liver cancer, PIM2 has been described to directly interact with and phosphorylate cell cycle regulators, p21 WAF1/CIP1 (18) and p27 KIP1 (19), as well as the pro-apoptotic protein, BAD (20), thus facilitating cell survival by maintaining mitochondrial potential (21,22). Furthermore, PIM2 has been found to be involved in the negative regulation of the DNA damage response pathway (23) and mediate drug resistance (24,25), as well as invasion (26,27). In liver cancer, there is evidence to suggest that PIM2 expression is upregulated (28)(29)(30), e.g., by inhibiting apoptosis (29,30).…”

Section: Inhibition Of Pim2 In Liver Cancer Decreases Tumor Cell Prolmentioning

confidence: 99%

Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in�vitro and in�vivo primarily through the modulation of cell cycle progression

et al. 2019

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Liver cancer is the fourth leading cause of cancer-related mortality worldwide with limited therapeutic options. Thus, novel treatment strategies are urgently required. While the oncogenic kinase, proviral integration site for Moloney murine leukemia virus 2 (PIM2), has been shown to be overexpressed in liver cancer, little is known about the role of PIM2 in this tumor entity. In this study, we explored the functional relevance and therapeutic potential of PIM2 in liver cancer. Using PIM2-specific siRNAs, we examined the effects of PIM2 knockdown on proliferation (WST-1 assays and spheroid assays), 3D-colony formation and colony spread, apoptosis (flow cytometry and caspase 3/caspase 7 activity), as well as cell cycle progression (flow cytometry, RT-qPCR and western blot analysis) in the two liver cancer cell lines, HepG2 and Huh-7. In subcutaneous liver cancer xenografts, we assessed the effects of PIM2 knockdown on tumor growth via the systemic delivery of polyethylenimine (PEI)-complexed siRNA. The knockdown of PIM2 resulted in potent anti-proliferative effects in cells grown on plastic dishes, as well as in spheroids. This was due to G0/G1 cell cycle blockade and the subsequent downregulation of genes related to the S phase as well as the G2/M phase of the cell cycle, whereas the apoptotic rates remained unaltered. Furthermore, colony formation and colony spread were markedly inhibited by PIM2 knockdown. Notably, we found that HepG2 cells were more sensitive to PIM2 knockdown than the Huh-7 cells. In vivo, the therapeutic nanoparticle-mediated delivery of PIM2 siRNA led to profound anti-tumor effects in a liver cancer xenograft mouse model. On the whole, the findings of this study underscore the oncogenic role of PIM2 and emphasize the potential of targeted therapies based on the specific inhibition of PIM2 in liver cancer.

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Section: Inhibition Of Pim2 In Liver Cancer Decreases Tumor Cell Prolmentioning

confidence: 99%

Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in�vitro and in�vivo primarily through the modulation of cell cycle progression

et al. 2019

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“…Furthermore, accumulating lines of evidence have suggested that PIM kinases are important in the pathogenesis of MM. PIM kinases play a wide range of roles in MM pathogenesis including cell proliferation[18], survival[14], cell cycle dysregulation, oncogenic collaboration with c-Myc, DNA damage repair[19], and bone destruction[20, 21]. A phase 1 study of the novel pan-PIM kinase inhibitor (LGH447) showed encouraging single-agent activities in heavily pre-treated relapsed/refractory MM[22].…”

Section: Introductionmentioning

confidence: 99%

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

et al. 2019

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Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.

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“…This is in part mediated by PIM2 phosphorylation of its downstream targets TSC2 (and modulation of mTORC1 activity 19 ), the pro-apoptotic factor BAD and the protein translational inhibitor 4EBP1. PIM2 has also been implicated in the myeloma-mediated bone destruction via negative regulation of osteoblastogenesis 15 , 20 and more recently in the regulation of the essential DNA damage response pathway in myeloma 21 .…”

Section: Introductionmentioning

confidence: 99%

Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma

Nair

Caserta²,

Belko

et al. 2016

Leukemia

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The PIM kinase family (PIM1, 2 and 3) play a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2’s role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. Treatment with JP11646 in xenogeneic myeloma murine models demonstrated significant reduction in tumor burden and increased median survival. Altogether our findings suggest the existence of previously unrecognized feedback loop(s) where PIM2 kinase activity regulates PIM2 gene expression in malignant cells, and that JP11646 represents a novel class of PIM2 inhibitors that interdicts this feedback.

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Pim2 is important for regulating DNA damage response in multiple myeloma cells

Cited by 20 publications

References 21 publications

Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in�vitro and in�vivo primarily through the modulation of cell cycle progression

Inhibition of PIM2 in liver cancer decreases tumor cell proliferation in�vitro and in�vivo primarily through the modulation of cell cycle progression

Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade

Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma

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