Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway

Tao, Na-Na; Zhou, Hong-Zhong; Tang, Hua; Cai, Xue-Fei; Zhang, Wenlu; Ren, Ji-Hua; Zhou, Li; Chen, Xiang; Chen, Ke; Li, Wanyu; Liu, Bo; Yang, Qiuxia; Cheng, Sheng-Tao; Huang, Lixia; Huang, Aiping; Chen, Juan

doi:10.18632/oncotarget.10319

Cited by 39 publications

(27 citation statements)

References 36 publications

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“…Therefore, it is very important to identify a drug candidate that can replace or be used together with sorafenib. Tao et al have found that upregulation of SIRT3 expression can enhance the sensitivity of HCC cells to chemotherapeutic agents (26). In our study, we found that the upregulation of SIRT3 by transfection in HCC cells reduced cell proliferation and significantly increased sensitivity to sorafenib.…”

Section: Discussionsupporting

confidence: 64%

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Yoo

Lee

et al. 2019

Preprint

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Background : Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. To date, a few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Thus, this study aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and to discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression is downregulated in high glycolytic and proliferative HCC of human patients, xenograft model and HCC cell lines. We also demonstrated that SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phospho-Rb in HCC. In addition, combined treatment with sorafenib and PD0332991 showed a synergic anti-tumor effect in HCC cells. Conclusions: Taken together, our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be used for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

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Section: Discussionsupporting

confidence: 64%

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Yoo

Lee

et al. 2019

Preprint

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“…Only a recent study highlighted a decreased SIRT-3 expression after the treatment with doxorubicin, cisplatin, and sorafenib in different HCC cell lines, suggesting a regulatory role of the enzyme in the drug sensitivity of HCC cells [62].…”

Section: The Tumor Suppressor Role Of Sirt-3 In Hccmentioning

confidence: 99%

Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma

Matteis

Granato²,

Napolitano

et al. 2017

Dig Dis Sci

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Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD)-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.

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“…e In parallel, proliferation was assessed 48 h later using WST-1 assays. Data from six technical replicates were analyzed and expressed as the mean ± SD cells to chemotherapeutic agents [26]. In our study, we found that the upregulation of SIRT3 by transfection in HCC cells reduced cell proliferation and significantly increased sensitivity to sorafenib.…”

Section: Discussionmentioning

confidence: 70%

“…To date, SIRT3 is known as a tumor suppressor gene [23], and overexpression of SIRT3 reduces cell growth and proliferation in HCC [23,25,26]. SIRT3 also induces apoptosis in abnormal cells through the upregulation of MnSOD, p53, Bax, and Fas [19].…”

Section: Discussionmentioning

confidence: 99%

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Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Park

Kim

et al. 2020

BMC Cancer

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Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the antitumor effect in HCC cells. Conclusions: Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

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Sirtuin 3 enhanced drug sensitivity of human hepatoma cells through glutathione S-transferase pi 1/JNK signaling pathway

Cited by 39 publications

References 36 publications

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma

Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

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