Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Sato, Aya; Oya, Mototsugu; Ito, Keiichi; Mizuno, Ryuichi; Horiguchi, Yutaka; Umezawa, Kazuo; Hayakawa, Masamichi; Murai, Masaru

doi:10.3892/ijo.28.4.841

Cited by 22 publications

(26 citation statements)

References 22 publications

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“…Survivin has bi-functional roles; it drives cell division and inhibits apoptosis, as reported in renal cancer carcinoma 42 and lung cancer cells. 35 Furthermore, in vivo studies have suggested the role of survivin in the tumorigenesis of melanomas.…”

Section: Discussionmentioning

confidence: 95%

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Virrey

Guan

et al. 2008

The American Journal of Pathology

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Growing evidence suggests that survivin, a member of the inhibitor of apoptosis gene family, is responsible for drug resistance in cancer cells, yet little is known about its role in the endothelial cells of the tumor vasculature. We have previously reported that tumor-associated endothelial cells derived from gliomas (TuBECs) are resistant to anticancer chemotherapy whereas normal brain endothelial cells (BECs) are sensitive. The focus of this study is to investigate the mechanism behind this chemoresistance. Here we show that survivin is constitutively overexpressed in the glioma vasculature but not in the blood vessels of normal brain. To determine whether survivin contributes to TuBEC chemoresistance, we used a lentiviral siRNA system or the drug roscovitine to down-regulate survivin expression. Reduced levels of survivin sensitized TuBECs to the chemotherapeutic agents VP-16, paclitaxel, thapsigargin, and temozolomide. This cell death was mediated through caspases 7 and 4. Conversely, forced expression of survivin in BECs was protective against drug cytotoxicity. These data suggest that overexpression of survivin in endothelial cells serves as a protective mechanism that defends the vasculature from drug cytotoxicity. Our studies demonstrate that targeting survivin may be an effective approach to chemosensitization and anti-vascular therapy for brain tumors.

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Section: Discussionmentioning

confidence: 95%

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Virrey

Guan

et al. 2008

The American Journal of Pathology

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“…An inverse correlation between XIAP expression and RCC aggressiveness has been reported [18]. High levels of Survivin correlated with poor survival in RCC patients [19], and siRNAs targeting survivin sensitized renal cancer cells towards chemotherapeutic agents and inhibited cell proliferation [20]. The expression of Smac, an endogenous inhibitor of IAPs, was down-regulated in RCC and inversely correlated Research Article with tumor stage and grade.…”

Section: Discussionmentioning

confidence: 96%

Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis

Crnković-Mertens

Wagener

Semzow

et al. 2007

Cell. Mol. Life Sci.

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Cancer cells are typically characterized by apoptosis deficiency. In order to investigate a possible role for the anti-apoptotic livin gene in renal cell cancer (RCC), we analyzed its expression in tumor tissue samples and in RCC-derived cell lines. In addition, we studied the contribution of livin to the apoptotic resistance of RCC cells by RNA interference (RNAi). Livin gene expression was detected in a significant portion of RCC tumor tissue specimens (13/14, 92.9%) and tumor-derived cell lines (12/15, 80.0%). Moreover, targeted inhibition of livin by RNAi markedly sensitized RCC cells towards proapoptotic stimuli, such as UV irradiation or the chemotherapeutic drugs etoposide, 5-fluorouracil, and vinblastine. These effects were specific for livin expressing tumor cells. We conclude that livin can contribute significantly to the apoptosis resistance of RCC cells. Targeted inhibition of livin could represent a novel therapeutic strategy to increase the sensitivity of renal cancers towards pro-apoptotic agents.

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“…Survivin and XIAP are both important antiapoptotic proteins in renal cancer. Survivin has been reported to be associated with the proliferation of renal cancer cells (17) and is a potential molecular target for treating renal cancer (18)(19)(20). On the other hand, XIAP has been shown to be a prognostic marker in renal cancer (21).…”

Section: Discussionmentioning

confidence: 99%

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

2012

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Abstract. Our previous study showed that the combination of a histone deacetylase (HDAC) inhibitor and an HIV protease inhibitor is effective against renal cancer cells. Because HDAC inhibition disrupts the chaperon function of heat shock protein (HSP) 90, we hypothesized that the combination of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of HSP90, and the HIV protease inhibitor ritonavir would also act against renal cancer. The combination of 17-AAG and ritonavir induced apoptosis and inhibited the proliferation of renal cancer cells effectively. It also suppressed the expression of cyclin-dependent kinase 4 and cyclin D1, leading to the accumulation of the cells in the sub-G1 fraction. The expression of HSPs 27, 70 and 90 was increased by 17-AAG alone but reduced by 17-AAG combined with ritonavir. The combination decreased the expression of heat shock factor-1 (HSF-1), an HSP transcription factor, and this might be one of the mechanisms of the effect of the combination. We have also found that silencing of HSF-1 by siRNA inhibited the proliferation of renal cancer cells and that in surgically resected specimens the levels of HSF-1 expression in renal cancer tissue are higher than those in normal parenchyma. This is the first study showing the beneficial effect of combining 17-AAG and ritonavir and our data suggest that HSF-1 may be a novel therapeutic target in the treatment of renal cancer. IntroductionAlthough recently introduced novel anticancer agents such as inhibitors of tyrosine kinase (1,2) and the mammalian target of rapamycin (3) are promising against advanced renal cancer, new treatment approaches are needed because curative agents are not yet available.Inhibition of heat shock protein 90 (HSP90) destabilizes the cancer cell's aberrant protein subset, leading to protein degradation by proteasomes (4). The geldanamycin derivative 17-allylamino-17-demethoxy-geldanamycin (17-AAG) is the first HSP90 inhibitor to be used clinically (5). It seems to be a promising anticancer agent with a novel mechanism of action, but a phase II clinical trial investigating the efficacy of 17-AAG found it not to be effective against renal cancer (6).We have previously shown that the combination of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and the HIV protease inhibitor ritonavir is effective against renal cancer by inhibiting the HDAC function and expression, leading to extensive histone acetylation (7). SAHA inhibits HDAC6, and ablation of HDAC6 has been shown to induce hyperacetylation of HSP 90, disrupting its chaperone function (8,9). We therefore thought that combining ritonavir with 17-AAG would be more effective against renal cancer because 17-AAG could inhibit HSP90 function more directly than SAHA does.In the present study, we investigated the combined effect of 17-AAG and ritonavir against renal cancer by using renal cancer cell lines and found that the combination inhibited the renal cancer growth by inhibiting the expression of heat shock factor-1 (HSF-1), an HS...

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Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-γ and a novel NF-κB inhibitor

Cited by 22 publications

References 22 publications

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis

17-allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1

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