The essential role of PIM kinases in sarcoma growth and bone invasion

Narlik-Grassow, Maja; Blanco‐Aparicio, Carmen; Cecilia, Yolanda; Peregrina, Sandra; García-Serelde, Beatriz; Muñoz-Galván, Sandra; Cañamero, Marta; Carnero, Amancio

doi:10.1093/carcin/bgs176

Cited by 35 publications

(39 citation statements)

References 60 publications

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“…The inactivation of one PTEN allele also works in conjunction with hormone treatments to increase the severity of prostate, bladder, and ureteral urothelial hyperplasia (111–113). These findings are consistent with a study showing that the prostate epithelial cells of castrated PTEN(-/-) mice will undergo massive apoptosis, unless they are treated with an mTOR inhibitor (114).…”

Section: Pi3k Pathway In Human Tumorsmentioning

confidence: 99%

The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models

2014

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When PI3K (phosphatidylinositol-3 kinase) is activated by receptor tyrosine kinases, it phosphorylates PIP2 to generate PIP3 and activates the signaling pathway. Phosphatase and tensin homolog deleted on chromosome 10 dephosphorylates PIP3 to PIP2, and thus, negatively regulates the pathway. AKT (v-akt murine thymoma viral oncogene homolog; protein kinase B) is activated downstream of PIP3 and mediates physiological processes. Furthermore, substantial crosstalk exists with other signaling networks at all levels of the PI3K pathway. Because of its diverse array, gene mutations, and amplifications and also as a consequence of its central role in several signal transduction pathways, the PI3K-dependent axis is frequently activated in many tumors and is an attractive therapeutic target. The preclinical testing and analysis of these novel therapies requires appropriate and well-tailored systems. Mouse models in which this pathway has been genetically modified have been essential in understanding the role that this pathway plays in the tumorigenesis process. Here, we review cancer mouse models in which the PI3K/AKT pathway has been genetically modified.

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Section: Pi3k Pathway In Human Tumorsmentioning

confidence: 99%

The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models

2014

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“…Using the TKO mice generated by Mikkers et al, we explored whether the inhibition of specific isoforms is required to prevent the sarcomas induced by treatment with the carcinogen 3-methylcholanthrene (44). We showed that the absence of Pim2 and Pim3 greatly reduced sarcoma growth and that the extent of this reduction was similar to that observed in the absence of all three isoforms.…”

Section: Pim Knock-out Micementioning

confidence: 99%

Genetic Modeling of PIM Proteins in Cancer: Proviral Tagging and Cooperation with Oncogenes, Tumor Suppressor Genes, and Carcinogens

et al. 2014

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The PIM proteins, which were initially discovered as proviral insertion sites in Moloney-murine leukemia virus infection, are a family of highly homologous serine/threonine kinases that have been reported to be overexpressed in hematological malignancies and solid tumors. The PIM proteins have also been associated with metastasis and overall treatment responses and implicated in the regulation of apoptosis, metabolism, the cell cycle, and homing and migration, which makes these proteins interesting targets for anti-cancer drug discovery. The use of retroviral insertional mutagenesis and refined approaches such as complementation tagging has allowed the identification of myc, pim, and a third group of genes (including bmi1 and gfi1) as complementing genes in lymphomagenesis. Moreover, mouse modeling of human cancer has provided an understanding of the molecular pathways that are involved in tumor initiation and progression at the physiological level. In particular, genetically modified mice have allowed researchers to further elucidate the role of each of the Pim isoforms in various tumor types. PIM kinases have been identified as weak oncogenes because experimental overexpression in lymphoid tissue, prostate, and liver induces tumors at a relatively low incidence and with a long latency. However, very strong synergistic tumorigenicity between Pim1/2 and c-Myc and other oncogenes has been observed in lymphoid tissues. Mouse models have also been used to study whether the inhibition of specific PIM isoforms is required to prevent carcinogen-induced sarcomas, indicating that the absence of Pim2 and Pim3 greatly reduces sarcoma growth and bone invasion; the extent of this effect is similar to that observed in the absence of all three isoforms. This review will summarize some of the animal models that have been used to understand the isoform-specific contribution of PIM kinases to tumorigenesis.

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“…By decreasing the abundance of HSP90AA1 in cancer cells, 2-24a/Cu could decrease the stability of HSP90AA1 client proteins, many of which are critical in tumor initiation and metastasis. Consistent with this hypothesis, PIM1 (a client protein of HSP90AA1 that affects sarcoma growth and bone invasion [21, 22, 30, 31]) is rapidly decreased in the 2-24a/Cu-treated cells. Similarly, AKT1, which affects cell-cycle arrest and apoptosis [22], is concomitantly decreased in the 2-24a/Cu-treated cells.…”

Section: Discussionmentioning

confidence: 70%

“…PIM1 is a client protein of HSP90AA1 in oncogenesis [1], and plays important roles in sarcoma growth and bone invasion [21]. PIM1 protein was significantly decreased in the 2-24a/Cu-treated U2os and HeLa cells (Figure 4A and B).…”

Section: Resultsmentioning

confidence: 99%

A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells

et al. 2014

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BackgroundThe 90-kDa heat shock protein HSP90AA1 is critical for the stability of several proteins that are important for tumor progression and thus, is a promising target for cancer therapy. Selenosemicarbazone metal complexes have been shown to possess anticancer activity through an unknown molecular mechanism.MethodsThe MTT assay, fluorescence-activated cell sorting, and fluorescent microscopy were used to analyze the mechanism of the anti-cancer activity of the selenosemicarbazone metal complexes. Additionally, RNA-seq was applied to identify transcriptional gene changes, and in turn, the signaling pathways involved in the process of 2-24a/Cu-induced cell death. Last, the expression of HSP90AA1, HSPA1A, PIM1, and AKT proteins in 2-24a/Cu-treated cells were investigated by western blot analysis.ResultsA novel selenosemicarbazone copper complex (2-24a/Cu) efficiently induced G2/M arrest and was cytotoxic in cancer cells. 2-24a/Cu significantly induced oxidative stress in cancer cells. Interestingly, although RNA-seq revealed that the transcription of HSP90AA1 was increased in 2-24a/Cu-treated cells, western blotting showed that the expression of HSP90AA1 protein was significantly decreased in these cells. Furthermore, down-regulation of HSP90AA1 led to the degradation of its client proteins (PIM1 and AKT1), which are also cancer therapy targets.ConclusionOur results showed that 2-24a/Cu efficiently generates oxidative stress and down-regulates HSP90AA1 and its client proteins (PIM1, AKT1) in U2os and HeLa cells. These results demonstrate the potential application of this novel copper complex in cancer therapy.

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The essential role of PIM kinases in sarcoma growth and bone invasion

Cited by 35 publications

References 60 publications

The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models

The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models

Genetic Modeling of PIM Proteins in Cancer: Proviral Tagging and Cooperation with Oncogenes, Tumor Suppressor Genes, and Carcinogens

A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells

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