Emerging Roles of SIRT1 in Cancer Drug Resistance

Wang, Zhiqiang; Chen, Wenyong

doi:10.1177/1947601912473826

Cited by 77 publications

(64 citation statements)

References 131 publications

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“…34 The p53 protein is known to be an important target of deacetylation by SIRT1. 11,20 The DNA binding capacity of deacetylated p53 was previously shown to be reduced, 35 which promoted MDM2-mediated ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Asaka

Miyamoto

Yumura

et al. 2015

Laboratory Investigation

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Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (Po0.05), and its overexpression was associated with a shorter survival (Po0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.

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Section: Discussionmentioning

confidence: 99%

Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target

Asaka

Miyamoto

Yumura

et al. 2015

Laboratory Investigation

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“…Chemotherapeutic drug resistance can be either innate and/or acquired, and result in recurrent cancers often being more resistant to treatment [142]. Innate mechanisms are inherent features of the particular cancer that render it drug resistant, and share many of the same processes that that acquired resistance of relapsed cancer can utilize.…”

Section: Part 2 Mechanisms Behind Resistance To Cancer Therapymentioning

confidence: 99%

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

Truman

Garcı́a-Barros

Obeid

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

113

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Traditional methods of cancer treatment are limited in their efficacy due to both inherent and acquired factors. Many different studies have shown that the generation of ceramide in response to cytotoxic therapy is generally an important step leading to cell death. Cancer cells employ different methods to both limit ceramide generation and to remove ceramide in order to become resistant to treatment. Furthermore, sphingosine kinase activity, which phosphorylates sphingosine the product of ceramide hydrolysis, has been linked to multidrug resistance, and can act as a strong survival factor. This review will examine several of the most frequently used cancer therapies and their effect on both ceramide generation and the mechanisms employed to remove it. The development and use of inhibitors of sphingosine kinase will be focused upon as an example of how targeting sphingolipid metabolism may provide an effective means to improve treatment response rates and reduce associated treatment toxicity.

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“…HDAC inhibitors have been widely used in cancer treatment by inducing cell growth arrest and apoptosis, inhibiting angiogenesis, and regulating DNA repair and mitosis (Falkenberg and Johnstone, 2014;Lin and Fang, 2013;Spiegel et al, 2012;Wang and Chen, 2013). For example, Several HDAC inhibitors induce cell cycle arrest at G1 via induction of the cyclin-dependent kinase inhibitor p21 WAF/ CIP1 .…”

Section: Introductionmentioning

confidence: 99%