Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1

Xiao, Man-Yu; Li, Fang-Fang; Xie, Peng; Qi, Yan-Shuang; Xie, Jin-Bo; Pei, Wen-Jing; Luo, Hao-Tian; Guo, Mei; Gu, Yu-Long; Piao, Xiang-Lan

doi:10.1016/j.cbi.2023.110674

Cited by 6 publications

(5 citation statements)

References 78 publications

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“…As a mevalonate pathway regulator, HMGCS1 serves as an important target. Therefore, potential HMGCS1 inhibitors can be explored for the treatment of cancers including CSN6‐overexpressing HCC, such as Gypenosides [ 23 ] and ligustilide. [ 24 ] It will be an exciting avenue for using these inhibitors in cancer prevention or therapy; for examples, in HCC patients when CSN6/HMGCS1 expression was prognostically detrimental.…”

Section: Discussionmentioning

confidence: 99%

CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

Li,

Zhang,

Lyu

et al. 2024

Advanced Science

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Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl‐CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle‐type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6‐HMGCS1‐YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non‐alcoholic fatty liver diseases‐ associated HCC.

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Section: Discussionmentioning

confidence: 99%

CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

Li,

Zhang,

Lyu

et al. 2024

Advanced Science

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“…HMGCS1 is the first key enzyme of the mevalonate pathway that converts acetoacetyl-CoA to HMG-CoA [ 19 ]. Previous studies have demonstrated that HMGCS1 expression is associated with malignant progression in colon cancer, gastric cancer, hepatocellular carcinoma, cervical cancer and cutaneous squamous cell carcinomas [ 20 ]. Recent studies demonstrated that HMGCS1 is a potential metabolic target for the treatment of cancer [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms

Gu,

Ye,

Zhu

et al. 2024

J Transl Med

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Background Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown. Methods mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts. Results We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway. Conclusion Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.

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“…In addition to inhibiting metabolic diseases, blocking cholesterol biosynthesis could serve as a potential cancer prevention strategy. Gypenosides, the major constituent of Gynostemma pentaphyllum , disrupt cholesterol biosynthesis via HMGCS1 inhibition, consequently suppressing the proliferation and migration of the Huh-7 and Hep3B cell lines . The suppressive effect of phytochemicals on cholesterol biosynthesis has been suggested in a colorectal cancer model.…”

Section: Regulation Of Cholesterol Homeostasismentioning

confidence: 99%

“…Gypenosides, the major constituent of Gynostemma pentaphyllum , disrupt cholesterol biosynthesis via HMGCS1 inhibition, consequently suppressing the proliferation and migration of the Huh-7 and Hep3B cell lines. 19 The suppressive effect of phytochemicals on cholesterol biosynthesis has been suggested in a colorectal cancer model. The callus extract of Hibiscus syriacus L., which is rich in fumaric acid and denatonium benzoate, was found to mediate Notch signaling, which subsequently suppressed cholesterol synthesis.…”

Section: Regulation Of Cholesterol Homeostasismentioning

confidence: 99%

Exploring Phytochemical Mechanisms in the Prevention of Cholesterol Dysregulation: A Review

Weerawatanakorn,

Kamchonemenukool,

Koh

et al. 2024

J. Agric. Food Chem.

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Although cholesterol plays a key role in many physiological processes, its dysregulation can lead to several metabolic diseases. Statins are a group of drugs widely used to lower cholesterol levels and cardiovascular risk but may lead to several side effects in some patients. Therefore, the development of a plant-based therapeutic adjuvant with cholesterol-lowering activity is desirable. The maintenance of cholesterol homeostasis encompasses multiple steps, including biosynthesis and metabolism, uptake and transport, and bile acid metabolism; issues arising in any of these processes could contribute to the etiology of cholesterolrelated diseases. An increasing body of evidence strongly indicates the benefits of phytochemicals for cholesterol regulation; traditional Chinese medicines prove beneficial in some disease models, although more scientific investigations are needed to confirm their effectiveness. One of the main functions of cholesterol is bile acid biosynthesis, where most bile acids are recycled back to the liver. The composition of bile acid is partly modulated by gut microbes and could be harmful to the liver. In this regard, the reshaping effect of phytochemicals on gut microbiota has been widely reported in the literature for its significance. Therefore, we reviewed studies conducted over the past 5 years elucidating the regulatory effects of phytochemicals or herbal medicines on cholesterol metabolism. In addition, their effects on the recomposition of gut microbiota and bile acid metabolism due to modulation are discussed. This review aims to provide novel insights into the treatment of cholesterol dysregulation and the anticipated development of natural-based compounds in the near and far future.

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Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1

Cited by 6 publications

References 78 publications

CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

CSN6‐SPOP‐HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation

Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms

Exploring Phytochemical Mechanisms in the Prevention of Cholesterol Dysregulation: A Review

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