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

Abstract

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.

SIRT3 and Metabolic Reprogramming Mediate the Antiproliferative Effects of Whey in Human Colon Cancer Cells

“…Mitochondrial function, including metabolism, ATP generation and the oxidative stress response, is critically regulated by SIRT3 [24], the major deacetylase within the mitochondrial matrix acting as a tumor suppressor by inhibiting the Warburg effect [41,42]. SIRT3 orchestrates multiple pathways and acts differently in various types of cancer cells, as tumor suppressor but also as tumor promoter [18][19][20][21][22][23][24][25][26]. Intriguingly, in CRC, SIRT3 displays an oncogenic role by deacetylating SHMT2 [27], and acts as tumor suppressor by increasing ROS production and PINK1/Parkin/mitophagy axis activation [9].…”

“…Clinical studies on association between SIRT3 and tumorigenesis showed controversial results. In hepatocellular carcinoma, SIRT3 upregulation re-sensitizes to sorafenib treatment [18]. Moreover, SIRT3 activation by the Bcl-2 inhibitor ABT737 contributes to improve cisplatin resistance in ovarian cancer [19].…”

Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction

“…Therapeutic advances targeting sirtuins are currently being explored as studies suggest modulating SIRT3 abundance via Cyclin-dependent kinase (CDK) 4/6 inhibition may enhance HCC therapy when combined with sorafenib [193]. Furthermore, a mechanistic Further demonstrating the coordinated nature of subcellular sirtuin activities, the nonmitochondrial sirtuins (SIRT1, 6, and 7) have been shown to play roles in HCC.…”

Epigenetics of Sirtuins: Relevance to Hepatocellular Carcinoma

“…Recent studies have indicated that ROS regulates the progression, metastasis, DNA damage, and mitochondrial pathway in HCC [65,66]. Moreover, SIRT3 promotes the sensitivity of hepatocellular carcinoma cells to regorafenib by accelerating mitochondrial dysfunction [67,68]. Overall, the occurrence and development of HCC decrease the expression of SIRT3, thereby suggesting a new method to treat HCC.…”