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Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells.

ABSTRACT: Primary liver cancer is the third leading cause of cancer death in the world, and the lack of effective treatments is the main reason for the high mortality. Corosolic acid (CA) has been proved to have antitumor activity. In this study, we found that CA can sensitize liver cancer cells to ferroptosis, which is a regulated form of cell death characterized by iron-dependent lipid peroxides reaching lethal levels. Here, we revealed that CA can inhibit glutathione (GSH) synthesis via HERPUD1, decreasing the cellular GSH level and causing liver cancer cells to become more sensitive to ferroptosis. Mechanistically, further studies found that HERPUD1 reduced the ubiquitination of the GSS-associated E3 ubiquitin ligase MDM2, which promoted ubiquitination of GSS, thereby inhibiting GSH synthesis to increase ferroptosis susceptibility. Importantly, a mouse xenograft model also demonstrated that CA inhibits tumor growth via HERPUD1. Collectively, our findings suggesting that CA is a candidate component for the development of treatments against liver cancer.

SUBMITTER: Peng Y

PROVIDER: S-EPMC9424261 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells.

Peng Yingxiu Y Li Ning N Tang Feifeng F Qian Chunmei C Jia Tingting T Liu Jingjin J Xu Yanfeng Y

Cell death discovery 20220829 1

Primary liver cancer is the third leading cause of cancer death in the world, and the lack of effective treatments is the main reason for the high mortality. Corosolic acid (CA) has been proved to have antitumor activity. In this study, we found that CA can sensitize liver cancer cells to ferroptosis, which is a regulated form of cell death characterized by iron-dependent lipid peroxides reaching lethal levels. Here, we revealed that CA can inhibit glutathione (GSH) synthesis via HERPUD1, decrea ...[more]

PMID: 36038536

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Project description:BackgroundGastric cancer (GC) is a malignant tumor of the digestive tract originating from the epithelial cells of the gastric mucosa, which is highly invasive and heterogeneous, posing a serious threat to human health. In recent years, ferroptosis, as a novel mode of programmed cell death, has shown potential anticancer effects in tumor therapy. Total Astragalus saponins (TAS), a natural product derived from Astragalus membranaceus, have been shown to possess various pharmacological activities, including anticancer effects. This study aimed to investigate the effects of TAS on GC cells, focusing on the mechanism of action of its regulation of the silent information regulator 3 (SIRT3) in inducing ferroptosis in GC cells.MethodsWe treated SGC-7901 cells with TAS at concentrations of 50, 100, and 200 µg/mL. After TAS treatment, the SGC-7901 cells were transfected with a vector designed to knock down SIRT3 expression. We assessed cell proliferation, viability, and apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay), colony formation assay, and flow cytometry. SIRT3 expression was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Fe2+, malondialdehyde (MDA), lactate dehydrogenase (LDH), and superoxide dismutase assay kits were used to detect the level of reactive oxygen species (ROS) by fluorescent probe assay. Western blot was used to detect apoptosis-related proteins and SIRT3 protein expression.ResultsTAS dose-dependently inhibited SGC-7901 cell proliferation and viability (P<0.05) and induced apoptosis (P<0.05). TAS promoted the expression of SIRT3 and ACSL4 proteins (P<0.05), inhibited the expression of SLC7A11 and GPX4 proteins (P<0.05), and induced ferroptosis of SGC-7901 cells (P<0.05). Knockdown of the SIRT3 gene attenuated the effect of TAS treatment on ferroptosis (P<0.05).ConclusionsTAS has therapeutic potential for GC and can effectively inhibit the proliferation and viability of SGC-7901 cells, and the mechanism may be that TAS upregulates SIRT3 to promote the ferroptosis of SGC-7901 cells.

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Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells.

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Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells.

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