Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation

Walpen, Thomas; Kalus, Ina; Schwaller, Jürg; Peier, Martin; Battegay, Edouard; Humar, Rok

doi:10.1016/j.bbrc.2012.10.106

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…A similar result was also obtained in tumor tissues from osteosarcoma patients. Signal transducer and activator of transcription (STAT) factors and PI3K/Akt pathway were demonstrated as the most important mediators of cytokines signaling, which are essential for PIM1 expression activation . Interestingly, our previous studies have shown that JAK‐STAT3 is overexpressed and activated in osteosarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…Our Western blot results showed that PIM1 was only detected as the 34 kDa isoform and exhibited predominantly nuclear staining in the TMA IHC and immunofluorescence. As nuclear accumulation of PIM1 is sufficient to increase cell growth, the high expression of the PIM1 34 kDa isoform may partly explain its important role in osteosacoma biological features …”

Section: Discussionmentioning

confidence: 99%

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Clinical and biological significance of PIM1 kinase in osteosarcoma

Liao

Feng

Shen

et al. 2015

Journal Orthopaedic Research

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Osteosarcoma is the most prevalent histological form of primary malignant bone tumor. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Proto-oncogene serine/ threonine-protein kinase PIM1 is associated with growth and survival of many kinds of tumor cells. However, the role of PIM1 in osteosarcoma remains largely unknown. In this study, we investigated the functional and therapeutic relevance of PIM1 as a putative target in osteosarcoma. We found PIM1 was highly expressed in various osteosarcoma cell lines and in tumor tissues from osteosarcoma patients. Tissue microarray and immunohistochemistry analysis showed that the overall and disease-free survival rate of patients with high levels of PIM1 protein expression were significantly shorter than patients with low levels. High levels of PIM1 were also associated with present metastasis and can be considered as an independent prognostic factor in osteosarcoma patients. Knockdown of PIM1 expression by synthetic siRNA or shRNA greatly inhibited cell growth, migration, and invasion. Moreover, these changes accompanied with down-regulation of anti-apoptotic protein Bcl-2. The similar results were obtained in osteosarcoma cells treated with PIM1 specific inhibitor (SMI-4a). These results suggest that PIM1 kinase is critical for the growth and metastasis of osteosarcoma cells and can be a potential therapeutic target for osteosarcoma treatment. ß

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical and biological significance of PIM1 kinase in osteosarcoma

Liao

Feng

Shen

et al. 2015

Journal Orthopaedic Research

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“…Previous studies suggested that irradiation can promote nuclear translocation of Pim-1 in radio-resistant squamocellular malignancies of head and neck [48]. Importantly, nuclear localization of Pim-1 may correlate with the proliferating cells and may also contribute to a survival response upon pathologic injury [49]. In our study, we transfected Myc-tagged Pim-1 with or without GFP-tagged EBNA3C expression vectors in HEK-293 cells.…”

Section: Resultsmentioning

confidence: 84%

EBNA3C Augments Pim-1 Mediated Phosphorylation and Degradation of p21 to Promote B-Cell Proliferation

Banerjee

Cai

et al. 2014

PLoS Pathog

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Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers.

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“…PIM1 is overexpressed in numerous solid tumors including prostate cancers (1, 2, 32) and has been known to play significant roles in tumorigenesis and chemoresistance in various cancers cells (33–36). As such, a number of PIM1 inhibitors have been developed (37), however most of these have not been tested yet either in in vitro or in vivo .…”

Section: Discussionmentioning

confidence: 99%

RNAi Screen Identifies a Synthetic Lethal Interaction between PIM1 Overexpression and PLK1 Inhibition

Meer

Song

Park

et al. 2014

Clinical Cancer Research

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Purpose To identify genes whose depletion is detrimental to Pim1-overexpressing prostate cancer cells and to validate this finding in vitro and in vivo. Experimental Design RNAi screening was employed to identify genes whose depletion is detrimental to Pim1-overexpressing cells. Our finding was validated using shRNA or PLK1 specific inhibitor BI 2536. Xenograft studies were performed using both PLK1 knockdown cells and BI 2536 to investigate the effects of PLK1 inhibition on tumorigenesis in Pim1-overexpressing cells. Finally, PLK1 and PIM1 expression patterns in human prostate tumors were examined by immunohistochemistry using tissue microarrays. Results We identified the mitotic regulator polo-like kinase (PLK1) as a gene whose depletion is particularly detrimental to the viability of Pim1-overexpressing prostate cancer. Inhibition of PLK1 by shRNA or BI 2536 in Pim1-overexpressing prostate cancer xenograft models resulted in a dramatic inhibition of tumor progression. Notably, Pim1-overexpressing cells were more prone to mitotic arrest followed by apoptosis due to PLK1 inhibition than control cells. Furthermore, inhibition of PLK1 led to the reduction of MYC protein levels both in vitro and in vivo. Our data also suggest that PIM1 and PLK1 physically interact and PIM1 might phosphorylate PLK1. Finally, PLK1 and PIM1 are frequently co-expressed in human prostate tumors, and co-expression of PLK1 and PIM1 was significantly correlated to higher Gleason grades. Conclusions Our findings demonstrate that PIM1-overexpressing cancer cells are particularly sensitive to PLK1 inhibition, suggesting that PIM1 might be used as a marker for identifying patients that will benefit from PLK1 inhibitor treatment.

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Nuclear PIM1 confers resistance to rapamycin-impaired endothelial proliferation

Cited by 10 publications

References 31 publications

Clinical and biological significance of PIM1 kinase in osteosarcoma

Clinical and biological significance of PIM1 kinase in osteosarcoma

EBNA3C Augments Pim-1 Mediated Phosphorylation and Degradation of p21 to Promote B-Cell Proliferation

RNAi Screen Identifies a Synthetic Lethal Interaction between PIM1 Overexpression and PLK1 Inhibition

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