Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells

Goyal, Himanshi; Sharma, Rati; Lamba, Dikshit; Kaur, Jyotdeep

doi:10.1007/s11010-022-04651-6

Cited by 6 publications

(5 citation statements)

References 30 publications

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“…Furthermore, FA supplementation can intensify the endoplasmic reticulum stress in tumour cells, enhancing their survival and metastatic potential. 121 In conclusion, low FA levels may correlate with HCC and liver fibrosis development. Optimal FA concentrations can help cancer prevention, yet excessive levels could contribute to cancer promotion.…”

Section: Excess Folic Acid May Promote Tumour Progressionmentioning

confidence: 87%

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The relationship between folic acid and nonalcoholic fatty liver disease

Xu,

Yang,

Zhu

et al. 2024

Clinical and Translational Dis

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In recent years, the incidence of non‐alcoholic fatty liver disease (NAFLD) has been increasing, which has become an explosive interest because of the growing impact on world health. NAFLD is the hepatic manifestation of systemic metabolic syndrome (MS), and the umbrella term that comprises a continuum of liver conditions, from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and hepatocellular carcinoma (HCC). currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folic acid (FA) was one of a water‐soluble B vitamins, entirely absorbed from the diet. Numbers of clinical studies have confirmed that patients with NAFLD and insulin resistance are often accompanied by abnormal FA. We investigated the potential effects of FA on NAFLD through the metabolic pathways, DNA synthesis and methylation, oxidative stress in liver and intestinal flora. In addition, FA has an effect on HCC or other cancer. Therefore, FA might be a safe and economical potential treatment method for NAFLD.

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Section: Excess Folic Acid May Promote Tumour Progressionmentioning

confidence: 87%

“…The underlying mechanism may involve excessive FA depleting MTHFR, creating a “methyl trap” that interferes with normal DNA methylation regulation. Furthermore, FA supplementation can intensify the endoplasmic reticulum stress in tumour cells, enhancing their survival and metastatic potential 121 …”

Section: Folic Acid and Cancermentioning

confidence: 99%

The relationship between folic acid and nonalcoholic fatty liver disease

Xu,

Yang,

Zhu

et al. 2024

Clinical and Translational Dis

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“…GSK2606414, a highly potent ATP-competitive PERK inhibitor through targeting the inactive DFG (Asp-Phe-Gly) conformation in the ATP binding region of PERK, was developed and could inhibit the subcutaneous tumor xenograft growth of human pancreatic ductal adenocarcinoma (PDAC) cells BxPC3 [24], the organoid-based tumor xenografts growth of PDAC with high BZW1 level [25], and the phenotypic transition of cancerassociated fibroblasts in PDAC [26]. Inhibition of PERK by GSK2606414 was able to enhance simvastatin-temozolomide-induced cell death in human glioblastoma cells U87 [27], folate deficiency-induced cell apoptosis in human hepatocellular carcinoma cells HepG2 [28], and metformin-induced cell apoptosis in the human epithelial ovarian cancer cells PA-1 and OVCAR-3, but not in peripheral blood mononuclear cells and normal ovarian surface epithelial cells [29]. On the contrary, inhibition of PERK by GSK2606414 had protective effects on the photodynamic therapy of chlorin A-induced cell apoptosis in the human cholangiocarcinoma cells HuCCt1 and EGI-1 [30], heme oxygenase-1 inducer cobalt protoporphyrin, carbon monoxide donor CORM, microtubule disruptors taxol and nocodazole-induced cell apoptosis in human colon cancer cells COLO205 and HCT-15 [31,32], curcumin derivative WZ35-induced cell apoptosis in mouse colorectal cancer cells CT26 [33], and evodiamineinduced cell apoptosis in human renal cell carcinoma cells A498 [34], epithelial ovarian cancer cells A2780 and its cisplatin-resistant cells A2780CP [35].…”

Section: Discussionmentioning

confidence: 99%

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs

Yu,

Xu,

Wang

et al. 2023

Biomedicines

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Colorectal cancer is a common malignant tumor. A major factor in the high mortality rate of colorectal cancer is the emergence of multidrug resistance (MDR). Overexpression of the ABCG2 gene in cancer cells directly leads to MDR. Finding new inhibitors of ABCG2 may be an effective way to overcome drug resistance. We found that the compound GSK2606414 enhanced the sensitivity of the ABCG2 substrate to the chemotherapeutic drugs mitoxantrone and doxorubicin in ABCG2-overexpressing multidrug-resistant colorectal cancer cells by increasing their intracellular accumulation without affecting the protein expression of ABCG2. Molecular docking experiments predicted that GSK2606414 could stably bind in the drug-binding pocket of ABCG2. In conclusion, GSK2606414 can sensitize ABCG2-overexpressed multidrug-resistant colorectal cancer cells to chemotherapy drugs and can be used as a potential inhibitor of ABCG2.

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“…Liver cell injury and transformation can arise due to ER stress. By activating multiple signalling pathways, ER stress undermines the liver cell growth inhibition pathway, promotes cell cycle progression and facilitates cell proliferation, thereby fostering the malignant transformation of liver cells 14 . Additionally, ER stress can contribute to liver fibrosis and precancerous lesions.…”

Section: Introductionmentioning

confidence: 99%

“…By activating multiple signalling pathways, ER stress undermines the liver cell growth inhibition pathway, promotes cell cycle progression and facilitates cell proliferation, thereby fostering the malignant transformation of liver cells. 14 Additionally, ER stress can contribute to liver fibrosis and precancerous lesions. In conditions like chronic hepatitis, ER stress prompts the proliferation of mesenchymal cells (such as hepatic stellate cells), culminating in liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of FAM134B inhibits endoplasmic reticulum stress‐related degradation protein expression and promotes hepatocellular carcinogenesis

Wang,

Liu,

Gong

et al. 2023

J Cellular Molecular Medi

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Endoplasmic reticulum (ER) stress can stimulate the proliferation and metastasis of hepatocellular carcinoma (HCC) cells while hindering apoptosis and immune system function, but the molecular mechanism of ER stress in HCC has yet to be fully studied. We aim to investigate the molecular mechanism by which FAM134B inhibits autophagy of HCC cells by reducing the expression of ER stress‐related degradation proteins. Clinical samples were collected for this study. Normal liver cell lines HL7702 and Hep3B and Huh7 HCC cell lines were cultured. Construction of FAM134B knockdown cell line. Cell proliferation was measured using the CCK‐8 assay, while cell migration and invasion capabilities were detected using the plate colony formation assay. Flow cytometry was used to detect the apoptosis rate. Transmission electron microscopy was used to observe the formation of autophagosomes. qRT‐PCR and WB detective expression changes related to autophagy proteins. Finally, the expression of the relevant proteins was observed by immunohistochemistry. The expression of FAM134B was significantly increased in human liver cancer tissue and HCC cell lines Hep3B and Huh7. After the lentiviral vector was transfected into Hep3B cells with sh‐FAM134B, results showed that sh‐FAM134B could effectively inhibit Hep3B cell proliferation and promote HCC cell apoptosis. Meanwhile, sh‐FAM134B could effectively induce the autophagy of Hep3B liver cancer cells. Immunohistochemistry results showed that sh‐FAM134B could effectively induce ER stress. FAM134B inhibits HCC cell autophagy and promotes the progression of liver cancer by inhibiting the expression of ER stress‐related degradation factors such as DERL2, EDEM1, SEL1L and HRD1.

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Folic acid depletion along with inhibition of the PERK arm of endoplasmic reticulum stress pathway promotes a less aggressive phenotype of hepatocellular carcinoma cells

Cited by 6 publications

References 30 publications

The relationship between folic acid and nonalcoholic fatty liver disease

The relationship between folic acid and nonalcoholic fatty liver disease

GSK2606414 Sensitizes ABCG2-Overexpressing Multidrug-Resistant Colorectal Cancer Cells to Chemotherapeutic Drugs

Upregulation of FAM134B inhibits endoplasmic reticulum stress‐related degradation protein expression and promotes hepatocellular carcinogenesis

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