Regulation of survivin expression by IGF-1/mTOR signaling

Vaira, Valentina; Lee, C W; Goel, Hira Lal; Bòsari, Silvano; Languino, Lucia R.; Altieri, Dario C.

doi:10.1038/sj.onc.1210094

Cited by 166 publications

(150 citation statements)

References 38 publications

(53 reference statements)

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“…Activation of mTOR induces the translation of various oncogenic proteins such as cMyc and hypoxia-inducible factor-1a (HIF1a) that results in an increase in genes that promote angiogenesis (VEGF) and cell survival (survivin; refs. [12][13][14]. Consistent with mTOR's role in these processes, we have previously shown that inhibition of mTOR decreases survivin levels, which significantly contributes to its anticancer activity (15).…”

Section: Introductionsupporting

confidence: 54%

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

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Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation.

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Section: Introductionsupporting

confidence: 54%

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

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“…NF-κB activation also contributes to survivin expression, and likewise NF-κB inhibition downregulates survivin (51,52). The expression of survivin is regulated by several other molecular pathways such as mTOR, which is required for its stability and translation (53). Furthermore, it is important to note that some drugs may induce expression of survivin by activation of the PI3K pathway (54).…”

Section: Discussionmentioning

confidence: 99%

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Souza

Vasconcelos²,

Reis³

et al. 2011

Int J Oncol

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Abstract. Overexpression of P-glycoprotein (Pgp/ABCB1) in tumor cells is associated with a classic phenotype of multidrug resistance (MDR). Moreover, some members of the inhibitor of apoptosis protein (IAP) family, such as survivin, contribute to an apoptosis-resistant phenotype, by inhibiting chemotherapyinduced cell death and promoting MDR. By using Western blotting, qRT-PCR, Annexin V and immunofluorescence assays we have demonstrated a relationship between Pgp and survivin in a prior sensitive chronic myeloid leukemia (CML) cell line (K562). A high dose of vincristine induced a concomitant overexpression of Pgp and survivin, which was associated with a low apoptotic index in the K562 cell line. In addition, we observed a cytoplasmic co-localization of Pgp and survivin, suggesting a functional association between these two proteins in apoptosis control by a common mechanism. In summary, our data suggest that Pgp and survivin should be analyzed in aggregate because they may have significant impact on drug resistance in CML cells.

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“…Our data is consistent with previous studies supporting a critical role of PI-3K/ Akt signaling pathway in the induction of Survivin expression; however, the detailed mechanism of how PI-3K/Akt activation results in the upregulation of Survivin remains less understood. Recent studies suggest that activation of insulin-like growth factor 1/ insulinlike growth factor 1 receptor signaling increases Survivin levels independent of gene transcription, rather through an enhanced protein translation-induced by Akt/ mTOR/p70S6K1 signaling pathway (Vaira et al, 2007;Oh et al, 2008). Although regulating protein translation of target gene is one of the major mechanisms of miRNA to exert its biological functions, it has been reported that different isoforms of Akt regulate epithelial-mesenchymal transition by controlling expression of miR-200 family in cancer cells (Iliopoulos et al, 2009).…”

Section: Erbb3 Induces Survivin Expressionmentioning

confidence: 99%

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

et al. 2010

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The coexpression of erbB3 and erbB2 is frequently observed in breast cancer; and erbB3 has a critical role in erbB2 promotion of breast cancer progression and anti-estrogen resistance. In this study, we determine the role of erbB3 in erbB2-mediated paclitaxel resistance in breast cancer cells. The overexpression of exogenous erbB3 via either stable or transient transfection in erbB2-overexpressing, but not epidermal growth factor receptor (EGFR)-expressing, breast cancer cells significantly decreases paclitaxel-induced growth inhibition and apoptosis. Consistently, knockdown of erbB3 expression with a specific short hairpin RNA (shRNA) in breast cancer cells with coexpression of both erbB2 and erbB3 enhances paclitaxel-induced apoptosis evidenced by increased DNA fragmentation, poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3 and -8. Furthermore, while forced overexpression of erbB3 increases, specific knockdown of erbB3 decreases the expression levels of Survivin only in the erbB2-overexpressing breast cancer cells. Targeting Survivin with specific shRNA overcomes paclitaxel resistance without effect on the expression levels of either erbB2 or erbB3. Mechanistic studies indicate that the specific phosphoinositide 3-kinase (PI-3K), Akt and mammalian target of rapamycin (mTOR) inhibitors, but not the mitogen-activated protein kinase kinase (MEK) inhibitor, not only abrogate erbB3-mediated upregulation of Survivin, but also reinforce the erbB2/erbB3-coexpressing breast cancer cells to paclitaxel-induced growth inhibition. These data demonstrate that heterodimerization of erbB2/erbB3 is a prerequisite for erbB2 tyrosine kinase activation; and elevated expression of erbB3 is required for erbB2-mediated paclitaxel resistance in breast cancer cells via PI-3K/Akt/ mTOR signaling pathway-dependent upregulation of Survivin. Our studies suggest that new strategies targeting erbB3 or Survivin may enhance the efficacy of chemotherapeutic agents against erbB2-overexpressing breast cancer.

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Regulation of survivin expression by IGF-1/mTOR signaling

Cited by 166 publications

References 38 publications

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

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