Targeting survivin in cancer: the cell-signalling perspective

Kanwar, Jagat R.; Kamalapuram, Sishir K; Kanwar, Rupinder K.

doi:10.1016/j.drudis.2011.04.001

Cited by 107 publications

(99 citation statements)

References 83 publications

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“…49,50 Survivin participates to glioma radio-and chemotherapy resistance [50][51][52] and a selective inhibitor of survivin, YM155, is currently under clinical trials. [53][54][55] Beside the p53-dependent transcriptional control of survivin, other pathways including the PI3K/AKT or the integrin-linked kinase pathway driven by tyrosine kinase receptors or integrins 51,50,56 have been implicated in its regulation. Survivin is thus confirmed as a pertinent therapeutic target in GBM and strategies aiming to decrease its expression should be considered.…”

Section: Discussionmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

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Section: Discussionmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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“…Despite survivin and Bcl-2 each acting as apoptosis inhibitors, these proteins execute biological functions through various pathways that regulate cellular apoptosis (44). Survivin may directly interact with and suppress the terminal effector cell-death proteases, such as caspase-3 and caspase-7 (40), while Bcl-2 mainly prevents the release of cytochrome c and then blocks the progression of apoptosis (34).…”

Section: Discussionmentioning

confidence: 99%

Guggulsterone inhibits human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell growth by inducing caspase-dependent apoptosis and downregulation of survivin and Bcl-2 expression

et al. 2015

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Abstract. Guggulsterone has recently been reported to demonstrate anti-tumor effects in a variety of cancers. The present study aims to investigate the biological roles and underlying mechanism of the action of guggulsterone in cholangiocarcinoma. The immortalized human cholangiocarcinoma Sk-ChA-1 and Mz-ChA-1 cell lines were treated with various concentrations of the trans isomer of guggulsterone, Z-guggulsterone. Cellular proliferation was determined using the XTT assay. The apoptotic status of cholangiocarcinoma cells was assessed by Hoechst 33258 staining, DNA fragmentation assay and flow cytometry. Specific caspase inhibitor was used to explore the role of caspase in guggulsterone-induced apoptosis. A colorimetric assay was performed to measure the alterations of the activities of caspase-3, -8 and -9. Western blot analysis was used to detect the protein expression of survivin, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein and cleaved poly (adenosine diphosphate-ribose) polymerase (PARP). As revealed by the present data, guggulsterone significantly inhibited the growth of the two human cholangiocarcinoma cell lines by inducing cellular apoptosis. In addition, guggulsterone-induced apoptosis of cholangiocarcinoma cells was demonstrated to be partially inhibited by the caspase inhibitors z-VAD-fmk, z-LEHD-fmk and z-IETD-fmk, accompanied by the activation of caspases-3, -8 and -9, accumulation of cleaved PARP and decreased expression of survivin and Bcl-2. In conclusion, the present study demonstrated that guggulsterone was able to suppress the proliferation of cholangiocarcinoma by inducing caspase-dependent apoptosis and downregulating survivin and Bcl-2.

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“…Indeed, many tumor cell types express VEGF receptors. VEGF has been found to promote the growth of transformed cell lines in vitro (Masood et al, 2001) and to act as a survival factor for tumor cells by enhancing the expression of the antiapoptotic factors bcl-2 (Harmey & Bouchier-Hayes, 2002) and survivin (Kanwar et al, 2011). In this context, MM cells have been shown to express high amounts of VEGF, VEGF receptors and co-receptors both in vitro and in vivo, and VEGF has been demonstrated to act as an autocrine growth factor for this tumor cell type (Albonici et al, 2009;Ohta et al, 1999;Pompeo et al, 2009;Strizzi et al, 2001a).…”

Section: Vegfmentioning

confidence: 99%