CoChat
Sign Up
Cited by 26

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response

Xiao, Man-Yu, Pei, Wen-Jing, Li, Si, Li, Fang-Fang, Xie, Peng, Luo, Hao-Tian, Hyun Yoo, Hye, Piao, Xiang-Lan·2024·Bioorganic Chemistry
DOI 10.1016/j.bioorg.2024.107539
Open this paper in CoChat — free account

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor…

Overview

Integrity signals

Registry

Crossref · 10.1016/j.bioorg.2024.107539

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Citations

Cites

Show all 5 references

Research works printed but not linked: 58

  1. Kanwal, 2020, Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents, Hepatology, 71, 44, 10.1002/hep.30823 · DOI
  2. Dave, 2021, Comparative effectiveness of entecavir versus tenofovir for preventing hepatocellular carcinoma in patients with chronic hepatitis B: a systematic review and meta-analysis, Hepatology, 73, 68, 10.1002/hep.31267 · DOI
  3. Younossi, 2018, Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention, Nat. Rev. Gastroenterol. Hepatol., 15, 11, 10.1038/nrgastro.2017.109 · DOI · Paper page
  4. Ioannou, 2016, The role of cholesterol in the pathogenesis of NASH, Trends Endocrinol. Metab., 27, 84, 10.1016/j.tem.2015.11.008 · DOI · Paper page
  5. Zhou, 2021, Cholesterol metabolism: a double-edged sword in hepatocellular carcinoma, Front. Cell Dev. Biol., 9, 10.3389/fcell.2021.762828 · DOI
  6. Liu, 2018, Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target, Sci. Transl. Med., 10, eaap9840, 10.1126/scitranslmed.aap9840 · DOI · Paper page
  7. Henkel, 2017, Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol, Mol. Med., 23, 70, 10.2119/molmed.2016.00203 · DOI
  8. Solsona-Vilarrasa, 2019, Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes, Redox Biol., 24, 10.1016/j.redox.2019.101214 · DOI
  9. Gobel, 2020, Cholesterol and beyond - the role of the mevalonate pathway in cancer biology, Biochim. Biophys. Acta, 1873
  10. Jeong, 2018, Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease, Crit. Rev. Biochem. Mol. Biol., 53, 279, 10.1080/10409238.2018.1458070 · DOI
  11. Brown, 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, Cell, 89, 331, 10.1016/S0092-8674(00)80213-5 · DOI · Paper page
  12. Horton, 2002, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Invest., 109, 1125, 10.1172/JCI0215593 · DOI · Paper page
  13. Brown, 2009, Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL, J. Lipid Res., 50, S15, 10.1194/jlr.R800054-JLR200 · DOI · Paper page
  14. Min, 2012, Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease, Cell Metab., 15, 665, 10.1016/j.cmet.2012.04.004 · DOI
  15. Yamashita, 2009, Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma, J. Hepatol., 50, 100, 10.1016/j.jhep.2008.07.036 · DOI
  16. Wang, 2018, Intracellular hepatitis B virus increases hepatic cholesterol deposition in alcoholic fatty liver via hepatitis B core protein, J. Lipid Res., 59, 58, 10.1194/jlr.M079533 · DOI
  17. Kim, 2019, Prevention of hepatocellular carcinoma by statins: clinical evidence and plausible mechanisms, Semin. Liver Dis., 39, 141, 10.1055/s-0039-1679956 · DOI
  18. Wu, 2014, Determination by UPLC-MS of four dammarane-type saponins from heat-processed Gynostemma pentaphyllum, Biosci. Biotech. Bioch., 78, 311, 10.1080/09168451.2014.882751 · DOI
  19. Nguyen, 2021, Triterpenoids from the genus Gynostemma: chemistry and pharmacological activities, J. Ethnopharmacol., 268, 10.1016/j.jep.2020.113574 · DOI
  20. Li, 2016, Anti-cancer effects of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan), Chin. Med., 11, 43, 10.1186/s13020-016-0114-9 · DOI
  21. Lee, 2019, Gynostemma pentaphyllum extract ameliorates high-fat diet-induced obesity in C57BL/6N mice by upregulating SIRT1, Nutrients, 11, 2475, 10.3390/nu11102475 · DOI
  22. Bae, 2018, Gypenoside UL4-rich gynostemma pentaphyllum extract exerts a hepatoprotective effect on diet-induced nonalcoholic fatty liver disease, Am. J. Chin. Med., 46, 1315, 10.1142/S0192415X18500696 · DOI
  23. Seo, 2017, Chemical constituents from a Gynostemma laxum and their antioxidant and neuroprotective activities, Chin. Med., 12, 15, 10.1186/s13020-017-0136-y · DOI
  24. Xie, 2023, Saponins derived from Gynostemma pentaphyllum regulate triglyceride and cholesterol metabolism and the mechanisms: a review, J. Ethnopharmacol., 319
  25. Xiao, 2023, Gypenosides suppress hepatocellular carcinoma cells by blocking cholesterol biosynthesis through inhibition of MVA pathway enzyme HMGCS1, Chem. Biol. Interact., 383, 10.1016/j.cbi.2023.110674 · DOI
  26. Liu, 2022, Gypenoside L and gypenoside LI inhibit proliferation in renal cell carcinoma via regulation of the MAPK and arachidonic acid metabolism pathways, Front. Pharmacol., 13
  27. Ma, 2019, Gypenoside L inhibits proliferation of liver and esophageal cancer cells by inducing senescence, Molecules, 24, 1054, 10.3390/molecules24061054 · DOI
  28. Zheng, 2016, Gypenoside L, isolated from gynostemma pentaphyllum, induces cytoplasmic vacuolation death in hepatocellular carcinoma cells through reactive-oxygen-species-mediated unfolded protein response, J. Agric. Food Chem., 64, 1702, 10.1021/acs.jafc.5b05668 · DOI
  29. Xing, 2018, The inhibitory effect of gypenoside stereoisomers, gypenoside L and gypenoside LI, isolated from Gynostemma pentaphyllum on the growth of human lung cancer A549 cells, J. Ethnopharmacol., 219, 161, 10.1016/j.jep.2018.03.012 · DOI
  30. He, 2023, The combination of R848 with sorafenib enhances antitumor effects by reprogramming the tumor immune microenvironment and facilitating vascular normalization in hepatocellular carcinoma, Adv Sci (Weinh), 10, e2207650, 10.1002/advs.202207650 · DOI
  31. King, 2022, The cholesterol pathway: impact on immunity and cancer, Trends Immunol., 43, 78, 10.1016/j.it.2021.11.007 · DOI
  32. Chen, 2023, Cholesterol Metabolism in cancer and cell death, Antioxid. Redox Signal., 39, 102, 10.1089/ars.2023.0340 · DOI
  33. Wang, 2019, Cholesterol regulates cell proliferation and apoptosis of colorectal cancer by modulating miR-33a-PIM3 pathway, Biochem. Biophys. Res. Commun., 511, 685, 10.1016/j.bbrc.2019.02.123 · DOI
  34. Gao, 2021, CRISPR screens identify cholesterol biosynthesis as a therapeutic target on stemness and drug resistance of colon cancer, Oncogene, 40, 6601, 10.1038/s41388-021-01882-7 · DOI
  35. Riscal, 2021, Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma, Cancer Discov., 11, 3106, 10.1158/2159-8290.CD-21-0211 · DOI
  36. Chen, 2023, Integrated multi-dimensional analysis highlights DHCR7 mutations involving in cholesterol biosynthesis and contributing therapy of gastric cancer, J. Exp. Clin. Cancer Res., 42, 36, 10.1186/s13046-023-02611-6 · DOI
  37. Liang, 2019, ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma, Cell Death Dis., 10, 830, 10.1038/s41419-019-2054-7 · DOI
  38. Sheikholeslami, 2019, Simvastatin induces apoptosis in medulloblastoma brain tumor cells via mevalonate cascade prenylation substrates, Cancers (Basel), 11, 994, 10.3390/cancers11070994 · DOI
  39. Gobel, 2020, Anti-tumor effects of mevalonate pathway inhibition in ovarian cancer, BMC Cancer, 20, 703, 10.1186/s12885-020-07164-x · DOI
  40. Lange, 2021, Prevention of NAFLD-associated HCC: Role of lifestyle and chemoprevention, J. Hepatol., 75, 1217, 10.1016/j.jhep.2021.07.025 · DOI
  41. Paul, 2022, Lipid alterations in chronic liver disease and liver cancer, JHEP Rep, 4
  42. Jiang, 2020, Alterations in glycolytic/cholesterogenic gene expression in hepatocellular carcinoma, Aging (Albany NY), 12, 10300, 10.18632/aging.103254 · DOI
  43. Yin, 2020, Ten new dammarane-type saponins with hypolipidemia activity from a functional herbal tea-gynostemma pentaphyllum, Molecules, 25, 3737, 10.3390/molecules25163737 · DOI
  44. Liu, 2023, Effects of gypenoside XLIX on fatty liver cell gene expression in vitro: a genome-wide analysis, Am. J. Transl. Res., 15, 834
  45. Wang, 2021, Gypenoside LVI improves hepatic LDL uptake by decreasing PCSK9 and upregulating LDLR expression, Phytomedicine, 91, 10.1016/j.phymed.2021.153688 · DOI
  46. Yang, 2017, Gypenoside XVII prevents atherosclerosis by attenuating endothelial apoptosis and oxidative stress: insight into the ERalpha-mediated PI3K/Akt pathway, Int. J. Mol. Sci., 18, 77, 10.3390/ijms18020077 · DOI
  47. Xie, 2020, The triterpenoid sapogenin (2alpha-OH-Protopanoxadiol) ameliorates metabolic syndrome via the intestinal FXR/GLP-1 axis through gut microbiota remodelling, Cell Death Dis., 11, 770, 10.1038/s41419-020-02974-0 · DOI
  48. Liu, 2021, Mechanism of gypenosides of Gynostemma pentaphyllum inducing apoptosis of renal cell carcinoma by PI3K/AKT/mTOR pathway, J. Ethnopharmacol., 271, 10.1016/j.jep.2021.113907 · DOI
  49. Zu, 2020, Monomer gypenoside LI from Gynostemma pentaphyllum inhibits cell proliferation and upregulates expression of miR-128-3p in melanoma cells, J. Biochem. Mol. Toxicol., 34, e22460, 10.1002/jbt.22460 · DOI
  50. Huang, 2022, Gypenoside A from gynostemma pentaphyllum attenuates airway inflammation and Th2 cell activities in a murine asthma model, Int. J. Mol. Sci., 23, 7699, 10.3390/ijms23147699 · DOI
  51. Yang, 2021, Gypenoside XLIX protects against acute kidney injury by suppressing IGFBP7/IGF1R-mediated programmed cell death and inflammation, Phytomedicine, 85, 10.1016/j.phymed.2021.153541 · DOI
  52. Wu, 2024, Gypenoside induces apoptosis by inhibiting the PI3K/AKT/mTOR pathway and enhances T-cell antitumor immunity by inhibiting PD-L1 in gastric cancer, Front. Pharmacol., 15, 1243353, 10.3389/fphar.2024.1243353 · DOI
  53. Lim, 2021, Lipid signalling enforces functional specialization of T(reg) cells in tumours, Nature, 591, 306, 10.1038/s41586-021-03235-6 · DOI
  54. York, 2015, Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling, Cell, 163, 1716, 10.1016/j.cell.2015.11.045 · DOI · Paper page
  55. Gruenbacher, 2010, IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56+ dendritic cells, Cancer Res., 70, 9611, 10.1158/0008-5472.CAN-10-1968 · DOI
  56. Hoppstadter, 2021, Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages, EBioMedicine, 72, 10.1016/j.ebiom.2021.103578 · DOI
  57. Sag, 2015, The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity, Nat. Commun., 6, 6354, 10.1038/ncomms7354 · DOI · Paper page
  58. Duan, 2021, Simultaneous quantitative analysis of nine saponins in Gynostemma pentaphyllum before and after heat processing based on UPLC-Q-Trap-MS, Zhongguo Zhong Yao Za Zhi, 46, 5314

Cited by

Sorted by citations

Metadata

Authors
Xiao, M.-Y., Pei, W.-J., Li, S., Li, F.-F., Xie, P., Luo, H.-T., Hyun Yoo, H., & Piao, X.-L.
Venue
Bioorganic Chemistry
Publisher
Elsevier BV
Published
2024-09
Volume
150
Pages
107539
ISSN
0045-2068
DOI
10.1016/j.bioorg.2024.107539
Cited by
26
References
5
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review