Cholesterol induces autophagic and apoptotic death in gastric carcinoma cells

Lim, Sung‐Chul; Parajuli, Keshab Raj; Duong, Hong‐Quan; Choi, Jeong Eun

doi:10.3892/ijo.2014.2246

Cited by 28 publications

(21 citation statements)

References 30 publications

(24 reference statements)

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“…While it did not influence MAP1LC3B mRNA expression, it did reduce LC3B-II, likely as a result of the absence of ATG5, a key component of the LC3B-II binary complex. To corroborate our findings, previous studies have shown the relationship between cholesterol synthesis or SREBP2 and autophagy [37,38]. SREBP2 directly binds to the promoter of several murine autophagy genes, such as Map1lc3b, Atb4b, and Atg4d, and SREBF2 knockout disrupts autophagosome formation in nutrient starvation in mouse models [37].…”

Section: Discussionsupporting

confidence: 89%

“…SREBP2 directly binds to the promoter of several murine autophagy genes, such as Map1lc3b, Atb4b, and Atg4d, and SREBF2 knockout disrupts autophagosome formation in nutrient starvation in mouse models [37]. Gastric cancer cells also represent a case where cholesterol supplement in the culture media decreased cell viability and clonogenicity via both autophagy and apoptosis [38]. In our results, it is not clear whether autophagy was induced by direct activation via SREBF2 binding to the promoters of autophagy genes or by cholesterol supplement for autophagosome formation.…”

Section: Discussionmentioning

confidence: 99%

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EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

Kim

Choi

Lim

et al. 2020

IJMS

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Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes monoand di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

Kim

Choi

Lim

et al. 2020

IJMS

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“…3D-E). Although the mitochondrial dysfunctions induced by cholesterol may promote apoptosis through the intrinsic pathway, the contribution of the extrinsic pathway of apoptosis induced by cholesterol through the activation of death receptors cannot be ruled out [45]. In addition to the protection against cholesterol-induced apoptosis by the prevention of mitochondrial dysfunction and cytochrome c release, QUE may exert protective effects by increasing Sirt1 expression.…”

Section: Discussionmentioning

confidence: 99%

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies

et al. 2016

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Studying rats fed high cholesterol diet and a pancreatic β-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic β-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NFκB pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic β-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NFκB pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on β-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve β-cell function.

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“…The current treatments for gastric cancer include surgery, chemotherapy, radiotherapy, thermal therapy, immune therapy, and Chinese herbal treatment. However, due to the difficulty in diagnosing gastric cancer at an early stage, the prognosis with the current treatment options is often poor (4,5). Therefore, it is necessary to identify novel agents that more effectively treat advanced gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of autophagy enhances cinobufagin‑induced apoptosis in gastric cancer

et al. 2018

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Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad Bufo gargarizans. Cinobufagin is one of the active ingredients in the anticancer Chinese medicine called Chan Su, which was demonstrated to be an effective treatment for gastric cancer. Increasing evidence shows that inhibition of autophagy has a pro-apoptotic effect on human gastric cancer cells. The aim of the present study was to investigate the relationship between cinobufagin, autophagy and apoptosis in gastric cancer. Autophagy was induced or inhibited in the human gastric cancer cell line SGC-7901 by incubation in HBSS media or by treatment with 3-methyladenine or ATG5 siRNA, respectively. Following treatment, the levels of apoptosis, apoptotic proteins, reactive oxygen species (ROS), and mitochondrial membrane potential were compared between the conditions. As anticipated, we found that cinobufagin increased apoptosis in SGC-7901 cells. Notably, inhibition of autophagy, monitored by the absence of the autophagosome marker LC3-II, also enhanced cell apoptosis. This effect was reversed when autophagy was induced by incubation in HBSS media. Enhanced expression of pro-apoptotic indicators, including BAX, cytosolic cytochrome c, cleaved PARP, caspase-3 and caspase-9, was detected when autophagy was suppressed. Increased pro-apoptotic protein expression was accompanied by disrupted mitochondrial membrane potential and elevated ROS production. Altogether, these data suggest that inhibition of autophagy enhances the anticancer action of cinobufagin through increased apoptosis of gastric cancer cells. Moreover, these effects may be partly mediated by ROS generation and the activation of the mitochondrial programmed cell death pathway.

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Cholesterol induces autophagic and apoptotic death in gastric carcinoma cells

Cited by 28 publications

References 30 publications

EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies

Inhibition of autophagy enhances cinobufagin‑induced apoptosis in gastric cancer

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