FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308386314> ?p ?o ?g. }

• W4308386314 endingPage "102678" @default.
• W4308386314 startingPage "102678" @default.
• W4308386314 abstract "Metformin, an antidiabetic drug, shows some potent antitumor effects. However, the molecular mechanism of metformin in tumor suppression has not been clarified. Here, we provided evidence using in vitro and in vivo data that metformin inhibited mevalonate pathway by downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), a key enzyme in this pathway. Our results further demonstrated that metformin downregulated HMGCS1 expression through inhibition of transcription factor nuclear factor E2–related factor 2. In addition, we determined that HMGCS1 was highly expressed in human liver and lung cancer tissues and associated with lower survival rates. In summary, our study indicated that metformin suppresses tumorigenesis through inhibition of the nuclear factor E2–related factor 2–HMGCS1 axis, which might be a potential target in cancer prevention and treatment. Metformin, an antidiabetic drug, shows some potent antitumor effects. However, the molecular mechanism of metformin in tumor suppression has not been clarified. Here, we provided evidence using in vitro and in vivo data that metformin inhibited mevalonate pathway by downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), a key enzyme in this pathway. Our results further demonstrated that metformin downregulated HMGCS1 expression through inhibition of transcription factor nuclear factor E2–related factor 2. In addition, we determined that HMGCS1 was highly expressed in human liver and lung cancer tissues and associated with lower survival rates. In summary, our study indicated that metformin suppresses tumorigenesis through inhibition of the nuclear factor E2–related factor 2–HMGCS1 axis, which might be a potential target in cancer prevention and treatment. Tumor growth and metastases need a constant and excessive supply of nutrients as building bricks, fuels, and signals so that altered nutrient metabolism is widely accepted to be added to the list of hallmarks of cancer (1Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (45613) Google Scholar). Among those nutrient sources, mevalonate pathway intermediates have been reported significantly accumulated in multiple tumors (2Mullen P.J. Yu R. Longo J. Archer M.C. Penn L.Z. The interplay between cell signalling and the mevalonate pathway in cancer.Nat. Rev. Cancer. 2016; 16: 718-731Crossref PubMed Scopus (379) Google Scholar). Recent studies reported that mevalonate pathway and its key enzyme 3-hydroxy-3-methylglutaryl-CoA receptor (HMGCR) had additional potent tumor-supportive effects besides sterol biosynthesis. Driven by oncogenes, such as mutant p53 (3Moon S.H. Huang C.H. Houlihan S.L. Regunath K. Freed-Pastor W.A. Morris J.P. et al.p53 represses the mevalonate pathway to mediate tumor suppression.Cell. 2019; 176: 564-580.e19Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar, 4Freed-Pastor W.A. Mizuno H. Zhao X. Langerød A. Moon S.H. Rodriguez-Barrueco R. et al.Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway.Cell. 2012; 148: 244-258Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar) and MYC (5Wang X. Huang Z. Wu Q. Prager B.C. Mack S.C. Yang K. et al.MYC-regulated mevalonate metabolism maintains brain tumor-initiating cells.Cancer Res. 2017; 77: 4947-4960Crossref PubMed Scopus (80) Google Scholar), the mevalonate flux plays a favorable role in several types of cancers. Several studies focus on the mevalonate flux’s role in the misfolded state and stability of tumor-suppressor gene p53 (6Parrales A. Ranjan A. Iyer S.V. Padhye S. Weir S.J. Roy A. et al.DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway.Nat. Cell Biol. 2016; 18: 1233-1243Crossref PubMed Scopus (152) Google Scholar, 7Ingallina E. Sorrentino G. Bertolio R. Lisek K. Zannini A. Azzolin L. et al.Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis.Nat. Cell Biol. 2018; 20: 28-35Crossref PubMed Scopus (87) Google Scholar), thus forming a positive feedback loop in tumor formation. The mevalonate pathway provides several intermediate products that are important to tumor growth, for example, ubiquinone to adjust redox control and mitochondrial activity during nutrient restriction, and squalene for prevention of oxidative cell death, bile acid (8Jia W. Xie G. Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat. Rev. Gastroenterol. Hepatol. 2018; 15: 111-128Crossref PubMed Scopus (901) Google Scholar) signaling, and its crosstalk with microbiota, let alone cholesterol, which is important for cell membrane formation and signal transduction in cancer cells (9Snaebjornsson M.T. Janaki-Raman S. Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer.Cell Metab. 2020; 31: 62-76Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar). Metformin, an oral hypoglycemic agent mainly prescribed to patients with type 2 diabetes, is known for its pleiotropic functions and safety. Besides the antidiabetic effects, metformin also shows the latent capacity to prevent and improve the prognosis of multiple cancer such as breast cancer (10Zakikhani M. Dowling R. Fantus I.G. Sonenberg N. Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.Cancer Res. 2006; 66: 10269-10273Crossref PubMed Scopus (902) Google Scholar) and prostate cancer (11Ben Sahra I. Laurent K. Loubat A. Giorgetti-Peraldi S. Colosetti P. Auberger P. et al.The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level.Oncogene. 2008; 27: 3576-3586Crossref PubMed Scopus (739) Google Scholar). According to ClinicalTrials.gov (https://clinicaltrials.gov/), 393 clinical trials are registered using metformin in the treatment of cancer till February 2022. Diabetes Prevention Program Outcomes Study demonstrated that metformin was associated with a 12% lower risk of cancer in a 22-year follow-up (12Lee C.G. Heckman-Stoddard B. Dabelea D. Gadde K.M. Ehrmann D. Ford L. et al.Effect of metformin and lifestyle interventions on mortality in the diabetes prevention Program and diabetes prevention Program Outcomes study.Diabetes Care. 2021; 44: 2775-2782Crossref PubMed Scopus (30) Google Scholar). After adjusting for age, gender, viral hepatitis, and other variables, metformin still reduced the incidence of hepatocellular carcinoma (HCC) (13Chen H.P. Shieh J.J. Chang C.C. Chen T.T. Lin J.T. Wu M.S. et al.Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies.Gut. 2013; 62: 606-615Crossref PubMed Scopus (327) Google Scholar). Since liver is a key organ for cholesterol homeostasis and bile production, it would be of interest to explore the effect of metformin on mevalonate pathway and HCC development. HCC accounts for nearly 90% of all liver cancers, casting heavy burden on public health and global economy (14Yang J.D. Hainaut P. Gores G.J. Amadou A. Plymoth A. Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management.Nat. Rev. Gastroenterol. Hepatol. 2019; 16: 589-604Crossref PubMed Scopus (1965) Google Scholar, 15Huang D.Q. El-serag H.B. Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 2020; 18: 223-238Crossref PubMed Scopus (658) Google Scholar). Therefore, there is an urgent need to identify the critical signaling pathways and molecular targets in the HCC for the prevention of progression and metastasis. To date, there is no report about metformin-induced suppression of tumorigenesis through inhibition of mevalonate pathway. Nuclear factor E2–related factor 2 (NRF2) is a transcription factor in oxidative stress response. NRF2 activation is reported to be associated with poor survival and tumor invasion of HCC (16Lee K. Kim S. Lee Y. Lee H. Lee Y. Park H. et al.The clinicopathological and prognostic significance of Nrf2 and Keap1 expression in hepatocellular carcinoma.Cancers (Basel). 2020; 12: 2128Crossref PubMed Scopus (10) Google Scholar). In this study, we investigated the role of mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in tumorigenesis and hypothesized that metformin functioned through inhibition of the NRF2–HMGCS1 axis to diminish tumor proliferation. Some pieces of research showed that metformin improved survival rate in patients with HCC (17Loomba R. Rationale for conducting a randomized trial to examine the efficacy of metformin in improving survival in cirrhosis: pleiotropic effects hypothesis.Hepatology. 2014; 60: 1818-1822Crossref PubMed Scopus (8) Google Scholar, 18de Oliveira S. Houseright R.A. Graves A.L. Golenberg N. Korte B.G. Miskolci V. et al.Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish.J. Hepatol. 2019; 70: 710-721Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar) through pleiotropic effects including the influence of cholesterol biosynthesis in cancer cells. We postulated that metformin may achieve this effect through the regulation of mevalonate pathway. We first checked the enzymes in the mevalonate pathway for their mRNA levels in HepG2 cells treated with metformin and verified that HMGCS1, rather than ACAT, HMGCR, HMGCS2, was the mere enzyme that underwent an expression change (Fig. 1, A and D). HepG2 cells treated with 20 mmol/l metformin for 48 h showed a time-dependent reduction (Fig. 1A) in mRNA level of HMGCS1 and was significantly reduced from 5 mmol/l to 20 mmol/l of metformin (Fig. 1B). There was a sharp decrease in the protein level of HMGCS1 while treated with 20 mmol/l metformin for 48 h (Fig. 1C). We used the ultraperformance liquid chromatography (UPLC)–MS to measure the contents of metabolites in the mevalonate pathway in hepG2 cell after metformin treatment (Fig. 1E). The concentrations of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) and mevalonic acid showed a significant decrease, whereas there was no significance change in acetyl-CoA and acetoacetyl-CoA concentrations. We then put emphasis on HMGCS1, the enzyme for HMG-CoA production. The inhibition of HMGCS1 expression by metformin was also observed in lung cancer cells A549 (Fig. S1A) and H1299 (Fig. S1B). These results show that metformin inhibits HMGCS1 expression in both mRNA and protein levels in liver cancer and lung cancer cell lines. To determine whether metformin regulates the expression of HMGCS1 through transcription factors, we conducted luciferase promoter assays in hepG2 cells and human embryonic kidney 293T (HEK293T) cells under the treatment of metformin (Fig. 2, A and B). We shortened the promoter activity region of HMGCS1 and narrowed down the binding sites of metformin on HMGCS1 to -267 to -838 (Fig. 2C). With the help of the PROMO website (19Messeguer X. Escudero R. Farré D. Núñez O. Martínez J. Albà M.M. Promo: detection of known transcription regulatory elements using species-tailored searches.Bioinformatics. 2002; 18: 333-334Crossref PubMed Scopus (992) Google Scholar), we found out several transcription factors that may work on the binding sites, including YY1, C/EBPalpha, C/EBPbeta, GR, and NRF2. By overexpressing each of these transcription factors in HEK293T cells, we found out only NRF2 upregulated the luciferase promoter assay of HMGCS1 (Fig. 2, D and E). Mutations of the two binding sites of NRF2 ceased its inhibition of HMGCS1 promoter by metformin (Fig. 2F). Chomatin immunoprecipitation (ChIP) provided further evidence between metformin treatment and the reduction in NRF2 and HMGCS1 combination (Fig. 2G). Since metformin did not change the mRNA expression of NRF2 (Fig. 2H), we examined the phosphorylation level of NRF2 to investigate the mechanism through which metformin inhibits NRF2. After treatment of metformin, phosphorylation levels of NRF2 were reduced in nuclear and cytosolic extracts of HepG2 cells, especially in the nucleus (Fig. 2I). We established NRF2-overexpressed A549 cells (Fig. S2A) and witnessed an increase in HMGCS1 mRNA levels (Fig. S2B). To elucidate whether NRF2 regulates the expression of endogenous HMGCS1, we used NRF2 activator oltipraz or NRF2 inhibitor ML385 (Fig. S2, C–E) in cancer cell lines. Oltipraz upregulated the expression of NRF2 downstream genes Npnt, Bmpr1a, and Igf1 as well as HMGCS1 (Fig. S2C), whereas ML385 led to the opposite trend, causing downregulation of Npnt and Igf1 together with HMGCS1 (Fig. S2D). Protein levels of endogenous HMGCS1 expression also changed synchronously with NRF2 (Fig. S2E). These results are consistent with the former data that oltipraz (20Zhou Y.Q. Liu D.Q. Chen S.P. Chen N. Sun J. Wang X.M. et al.Nrf2 activation ameliorates mechanical allodynia in paclitaxel-induced neuropathic pain.Acta Pharmacol. Sin. 2020; 41: 1041-1048Crossref PubMed Scopus (48) Google Scholar) and ML385 (21Singh A. Venkannagari S. Oh K.H. Zhang Y.Q. Rohde J.M. Liu L. et al.Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors.ACS Chem. Biol. 2016; 11: 3214-3225Crossref PubMed Scopus (314) Google Scholar), although known as activator and inhibitor of NRF2, which could also change the protein expression of NRF2. These results suggest that endogenous HMGCS1 can be transcriptionally regulated by NRF2 in response to metformin treatment. To determine whether the suppression of tumorigenesis by metformin depends on the inhibition of HMGCS1, we constructed overexpression plasmid of HMGCS1. Cell viability assessed by Cell Counting Kit-8 (Dojindo) was markedly restored after overexpressing HMGCS1 in HepG2 cells (Fig. 3A) and A549 cells (Fig. S3A). The percentage of apoptotic cells was soared with the treatment of metformin and returned to the baseline level by add-on of overexpression of HMGCS1 (Fig. S3, B and C). We further explored the antitumor activity of metformin in vivo. Transplanted tumor models in nude mice were established, using HepG2 cells and A549 cells transfected with HMGCS1 and control vectors, and treated with metformin (200 mg/kg) or solvent control by gastric perfusion and sacrificed to measure the volume and weight of tumors and relative gene expression. The first day of cell injection was recorded as day 0, and metformin was introduced from day 9, with a total observation period of 15 days. Tumor growth was suppressed by metformin in liver cancer (Fig. 3, B, D, and E) and lung cancer (Fig. S3, D–F), and the tumor-suppressing effect of metformin was reversed by HMGCS1 overexpression in nude mice xenograft models of both liver cancer (Fig. 3, C, D, and E) and lung cancer (Fig. S3, D, E, and G) without changing the weight of the mice (Figs. 3F and S3H). Based on these facts, we verify that the tumor-suppressive effect of metformin is mediated by mevalonate pathway key enzyme HMGCS1. To test the oncogenic role of HMGCS1, we used RNA interference of HMGCS1 in tumorigenicity assays. HepG2 cells (Fig. 4A) and A549 cells (Fig. S4A) were transfected with three different siRNA to knock down HMGCS1 for 4 days, respectively. RNA interference of HMGCS1 in both cell lines using potent KD2 siRNA demonstrated a marked tumor-suppressive effect, as shown in cell viability (Figs. 4B and S4B), bromodeoxyuridine proliferation assay (Figs. 4C and S4C), and cell cycle (Fig. 4D and S4D). RNA interference also led to tumor cell apoptosis (Figs. 4E and S4E). These findings collectively indicate that RNA interference of HMGCS1 imitates the effect of metformin. We have investigated the oncogenic role of HMGCS1 in liver cancer cells and animals. We further explored the role of HMGCS1 in human liver cancer. In human HCC samples, expression of HMGCS1 was markedly increased in mRNA levels (Fig. 5A) and protein levels by immunohistochemistry staining compared with the paired adjacent noncancerous tissues (Fig. 5B). Higher HMGCS1 expression in HCC tissues leads to a poor overall survival rate in HCC patients (Fig. 5C). Similar results were observed in the patients with lung cancer (Fig. S5, A–C). Several previous studies revealed the relationship between mevalonate pathway and tumor formation. In this study, we shed light on the tumor-suppressive role of metformin mediated by inhibition of mevalonate pathway enzyme HMGCS1. The mevalonate pathway exists in almost all cell types, so its oncogenic role and possibility as a drug target are worth further investigation. HMGCS1, the first key enzyme in mevalonate pathway, turns acetoacetyl-CoA into HMG-CoA, which further undergoes the catalysis of HMGCR to generate mevalonic acid. Jiang et al. (22Jiang X.N. Zhang Y. Wang W.G. Sheng D. Zhou X.Y. Li X.Q. Alteration of cholesterol metabolism by metformin is associated with improved outcome in type II diabetic patients with diffuse large B-cell lymphoma[J].Front. Oncol. 2021; 11608238Google Scholar) reported that HMGCS1 expression could be suppressed by metformin. Our results verified that HMGCS1 is an important target to mediate the antitumor activities of metformin. The expression levels of HMGCS1 and its downstream metabolite mevalonate decrease after treatment with metformin (Fig. 1), and this decrease is synchronizing with the cell viability and tumor growth (Fig. 3). We also confirm that HMGCS1 is highly expressed in human liver cancer and lung cancer tissues and related to poor prognosis and overall survival rate (Fig. 5). It is possible that increased HMGCS1 expression in tumor tissues might contribute to cell division, proliferation, and signal transduction. The mevalonate pathway contributes to the progression of several types of cancers through its key enzymes and metabolites. Some researches were consistent with our point of view by pointing out that HMGCS1 is highly expressed in most cancer types, and it is also related to the poor prognosis and drug resistance (23Zhou C. Wang Z. Cao Y. Zhao L. Pan-cancer analysis reveals the oncogenic role of 3-hydroxy-3-methylglutaryl-CoA synthase 1.Cancer Rep. 2021; 5: e1562Google Scholar). Other studies found out that HMGCR-driven MYC activation (24Cao Z. Fan-Minogue H. Bellovin D.I. Yevtodiyenko A. Arzeno J. Yang Q. et al.MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase.Cancer Res. 2011; 71: 2286-2297Crossref PubMed Scopus (140) Google Scholar) and cholesterol production (25Che L. Chi W. Qiao Y. Zhang J. Song X. Liu Y. et al.Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans.Gut. 2020; 69: 177-186Crossref PubMed Scopus (86) Google Scholar) supports the growth of liver cancer. Lipid reprogramming including regulation of HMGCS1 and HMGCR contributes to epithelial-to-mesenchymal transition in HCC and invasive phenotype like invadopodia formation. In a mouse xenograft model of HT29 human colon cancer cell line, mevalonate replenish experiment reversed the tumor-suppressing effect of metformin (26Seo Y. Kim J. Park S.J. Park J.J. Cheon J.H. Kim W.H. et al.Metformin suppresses cancer stem cells through AMPK activation and inhibition of protein prenylation of the mevalonate pathway in colorectal cancer.Cancers (Basel). 2020; 12: 2554Crossref PubMed Scopus (26) Google Scholar). This result is consistent with our HPLC/MS results (Fig. 1E) and verified our speculation that the presence of mevalonate is essential in tumor proliferation. Cell viability restored by mevalonic acid replenishment could be inhibited by metformin (Fig. S6). All these facts provide reasons why the inhibitors of the mevalonate pathway are under heated investigation for their antitumor activities (27Singh S. Singh P.P. Singh A.G. Murad M.H. Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis.Gastroenterology. 2013; 144: 323-332Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar, 28Nilsson S. Huelsenbeck J. Fritz G. Mevalonate pathway inhibitors affect anticancer drug-induced cell death and DNA damage response of human sarcoma cells.Cancer Lett. 2011; 304: 60-69Crossref PubMed Scopus (22) Google Scholar). Studies over the past decade revealed that metformin functions through inhibition of mammalian target of rapamycin (mTOR) to a great extent (29Ben Sahra I. Regazzetti C. Robert G. Laurent K. Le Marchand-Brustel Y. Auberger P. et al.Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1.Cancer Res. 2011; 71: 4366-4372Crossref PubMed Scopus (509) Google Scholar). It happened that an observation gave a clue for the metabolite mevalonate’s role in activation of mTOR (30Bekkering S. Arts R.J.W. Novakovic B. Kourtzelis I. van der Heijden C.D.C.C. Li Y. et al.Metabolic induction of trained immunity through the mevalonate pathway.Cell. 2018; 172: 135-146.e9Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar). Chances are that there is a convergence of the antitumor role of metformin and the mevalonate pathway, and mTOR is their shared downstream target. A study on renal cell carcinoma showed the additive effect of mevalonate pathway inhibitor statins and mTOR inhibitor (31Hagiwara N. Watanabe M. Iizuka-Ohashi M. Yokota I. Toriyama S. Sukeno M. et al.Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma.Cancer Lett. 2018; 431: 182-189Crossref PubMed Scopus (13) Google Scholar). Our study uncovers that the mevalonate pathway dependence is a common feature in liver cancer and lung cancer. Between the two lung cancer cell lines we used, A549 cells have more epithelial characteristics, whereas H1299 cells are derived from mesenchymal connective tissues. We also used HCC cell line SNU182 and hepatoblastoma cell line HepG2. These four tumor cell lines are from different tissues and origins, all demonstrating the same trend that mevalonate pathway together with cell activity can be inhibited by metformin. These results validate our hypothesis that the oncogenic role of mevalonate pathway and HMGCS1 is universal in multiple tumors. We speculate that the antitumor effect of metformin could be reproduced in other tumor cell lines and even tumors in vivo. Here, our results showed that HMGCS1 could be transcriptionally upregulated by NRF2. Previous studies reported NRF2 mutations and NRF2-Keap1 pathway activation throughout the hepatocarcinogenesis (32Orrù C. Szydlowska M. Taguchi K. Zavattari P. Perra A. Yamamoto M. et al.Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis.J. Hepatol. 2018; 69: 635-643Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). Constitutive NRF2 activation was observed in human cancer tissues (33Shibata T. Ohta T. Tong K.I. Kokubu A. Odogawa R. Tsuta K. et al.Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 13568-13573Crossref PubMed Scopus (596) Google Scholar). The elevated expression of NRF2 may serve as a compensatory mechanism to resist ischemia and subsequent hypoxia (34Ziv E. Zhang Y. Kelly L. Nikolovski I. Boas F.E. Erinjeri J.P. et al.NRF2 dysregulation in hepatocellular carcinoma and ischemia: a cohort study and laboratory investigation.Radiology. 2020; 297: 225-234Crossref PubMed Scopus (11) Google Scholar). We discovered that a large dose of metformin weakened the transcription activity of NRF2 by reducing its protein phosphorylation, leading to a decrease of HMGCS1 expression and tumor arrest. These observations are consistent with the established theory that NRF2 inhibitors are effective in treatment of aggressive tumors that grow rapidly and are resistant to treatment, whereas NRF2 inducers are used to protect normal cells from carcinogens through antioxidative effects (35Panieri E. Buha A. Telkoparan-Akillilar P. Cevik D. Kouretas D. Veskoukis A. et al.Potential applications of NRF2 modulators in cancer therapy.Antioxidants (Basel). 2020; 9: 193Crossref PubMed Scopus (86) Google Scholar). A piece of previous study showed that hmgcs1 gene was negatively regulated by Nrf2 in mice (36Hayes J.D. Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism.Trends Biochem. Sci. 2014; 39: 199-218Abstract Full Text Full Text PDF PubMed Scopus (1383) Google Scholar). To our knowledge, it is the first time to demonstrate that NRF2 regulates HMGCS1 through transcriptional activity in controlling cancer progression. We postulate that the change of phosphor-NRF2 under the treatment of metformin is probably induced by PKC λ/ι (37Kudo Y. Sugimoto M. Arias E. Kasashima H. Cordes T. Linares J.F. et al.Pkcλ/ι loss induces autophagy, oxidative phosphorylation, and NRF2 to promote liver cancer progression.Cancer Cell. 2020; 38: 247-262.e11Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 38Huang H.C. Nguyen T. Pickett C.B. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.J. Biol. Chem. 2002; 277: 42769-42774Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar) because we used an antibody specific for Nrf2 phosphorylated at S40. In previous studies, metformin not only inhibits the phosphorylation levels of Nrf2 (39Wang X. Li R. Zhao X. Yu X. Sun Q. Metformin promotes HaCaT cell apoptosis through generation of reactive oxygen species via raf-1-ERK1/2-Nrf2 inactivation.Inflammation. 2018; 41: 948-958Crossref PubMed Scopus (18) Google Scholar) but also mediates Nrf2 degradation (40Huang S. He T. Yang S. Sheng H. Tang X. Bao F. et al.Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2.Transl. Lung Cancer Res. 2020; 9: 2337-2355Crossref PubMed Scopus (26) Google Scholar). To sum up, this present study revealed the key role of the NRF2–HMGCS1 axis in the antitumor activity of metformin. Consistent with this notion, we assume that HMGCS1 might serve as a novel therapeutic target for liver cancer, which adds another piece to the puzzle of the relationship between metformin, cancer, and metabolism. In this research, mice that underwent a high dose of metformin remained the same weight, indicating that metformin suppresses the tumor progression at a safe dose without disturbance of energy metabolism or aggravation of cachexia. However, it should be noted that we used metformin with a dose beyond the physiological amount (41He L. Wondisford F.E. Metformin action: concentrations matter.Cell Metab. 2015; 21: 159-162Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). In this regard, more investigations are needed to show the potential of metformin within the regular dosage for patients. Targeting the delivery system of metformin to improve its therapeutic efficacy is worth equal attention. The targets we predicted using the PROMO website may not include all possible scenarios. Based on the transcriptional regulation role of GATA 1 on HMGCS1 in the process of erythropoiesis, further investigations can be made to determine the role of GATA 1 in regulation of HMGCS1 in the development of solid tumors (42Zhou C. Li J. Du J. Jiang X. Xu X. Liu Y. et al.HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis.Biomed. Pharmacother. 2021; 137111378Crossref Scopus (10) Google Scholar). Noteworthy, the downstream mechanism of HMGCS1-mediated tumor promotion function needs further investigation. In summary, we unveil that metformin suppresses tumor growth and progression through inhibition of mevalonate pathway enzyme HMGCS1 (Fig. 6). HMGCS1 also serves as a predictive biomarker of poor prognosis in patients with liver cancer and lung cancer." @default.
• W4308386314 created "2022-11-11" @default.
• W4308386314 creator A5011905011 @default.
• W4308386314 creator A5015723501 @default.
• W4308386314 creator A5048145081 @default.
• W4308386314 creator A5064313825 @default.
• W4308386314 creator A5082224986 @default.
• W4308386314 date "2022-12-01" @default.
• W4308386314 modified "2023-10-15" @default.
• W4308386314 title "Antidiabetic drug metformin suppresses tumorigenesis through inhibition of mevalonate pathway enzyme HMGCS1" @default.
• W4308386314 cites W1988005724 @default.
• W4308386314 cites W1998560601 @default.
• W4308386314 cites W2035676834 @default.
• W4308386314 cites W2053063855 @default.
• W4308386314 cites W2078190084 @default.
• W4308386314 cites W2080654617 @default.
• W4308386314 cites W2093664485 @default.
• W4308386314 cites W2116102471 @default.
• W4308386314 cites W2117692326 @default.
• W4308386314 cites W2134987468 @default.
• W4308386314 cites W2137443978 @default.
• W4308386314 cites W2150144117 @default.
• W4308386314 cites W2158373383 @default.
• W4308386314 cites W2164882663 @default.
• W4308386314 cites W2169285228 @default.
• W4308386314 cites W2515257966 @default.
• W4308386314 cites W2517092932 @default.
• W4308386314 cites W2532024005 @default.
• W4308386314 cites W2738778921 @default.
• W4308386314 cites W2761145411 @default.
• W4308386314 cites W2773500108 @default.
• W4308386314 cites W2782649526 @default.
• W4308386314 cites W2791613797 @default.
• W4308386314 cites W2801103679 @default.
• W4308386314 cites W2804389028 @default.
• W4308386314 cites W2903708727 @default.
• W4308386314 cites W2905891236 @default.
• W4308386314 cites W2925521234 @default.
• W4308386314 cites W2969802526 @default.
• W4308386314 cites W2994268592 @default.
• W4308386314 cites W3008752357 @default.
• W4308386314 cites W3011855728 @default.
• W4308386314 cites W3037387411 @default.
• W4308386314 cites W3046898116 @default.
• W4308386314 cites W3048530407 @default.
• W4308386314 cites W3084238062 @default.
• W4308386314 cites W3112263591 @default.
• W4308386314 cites W3117083078 @default.
• W4308386314 cites W3132021105 @default.
• W4308386314 cites W3210851898 @default.
• W4308386314 doi "https://doi.org/10.1016/j.jbc.2022.102678" @default.
• W4308386314 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36356901" @default.
• W4308386314 hasPublicationYear "2022" @default.
• W4308386314 type Work @default.
• W4308386314 citedByCount "2" @default.
• W4308386314 countsByYear W43083863142023 @default.
• W4308386314 crossrefType "journal-article" @default.
• W4308386314 hasAuthorship W4308386314A5011905011 @default.
• W4308386314 hasAuthorship W4308386314A5015723501 @default.
• W4308386314 hasAuthorship W4308386314A5048145081 @default.
• W4308386314 hasAuthorship W4308386314A5064313825 @default.
• W4308386314 hasAuthorship W4308386314A5082224986 @default.
• W4308386314 hasBestOaLocation W43083863141 @default.
• W4308386314 hasConcept C104317684 @default.
• W4308386314 hasConcept C134018914 @default.
• W4308386314 hasConcept C181199279 @default.
• W4308386314 hasConcept C185592680 @default.
• W4308386314 hasConcept C2779715943 @default.
• W4308386314 hasConcept C2779982574 @default.
• W4308386314 hasConcept C2780035454 @default.
• W4308386314 hasConcept C2780323712 @default.
• W4308386314 hasConcept C553450214 @default.
• W4308386314 hasConcept C55493867 @default.
• W4308386314 hasConcept C555283112 @default.
• W4308386314 hasConcept C555293320 @default.
• W4308386314 hasConcept C71924100 @default.
• W4308386314 hasConcept C98274493 @default.
• W4308386314 hasConceptScore W4308386314C104317684 @default.
• W4308386314 hasConceptScore W4308386314C134018914 @default.
• W4308386314 hasConceptScore W4308386314C181199279 @default.
• W4308386314 hasConceptScore W4308386314C185592680 @default.
• W4308386314 hasConceptScore W4308386314C2779715943 @default.
• W4308386314 hasConceptScore W4308386314C2779982574 @default.
• W4308386314 hasConceptScore W4308386314C2780035454 @default.
• W4308386314 hasConceptScore W4308386314C2780323712 @default.
• W4308386314 hasConceptScore W4308386314C553450214 @default.
• W4308386314 hasConceptScore W4308386314C55493867 @default.
• W4308386314 hasConceptScore W4308386314C555283112 @default.
• W4308386314 hasConceptScore W4308386314C555293320 @default.
• W4308386314 hasConceptScore W4308386314C71924100 @default.
• W4308386314 hasConceptScore W4308386314C98274493 @default.
• W4308386314 hasFunder F4320321001 @default.
• W4308386314 hasFunder F4320321540 @default.
• W4308386314 hasFunder F4320335777 @default.
• W4308386314 hasIssue "12" @default.
• W4308386314 hasLocation W43083863141 @default.
• W4308386314 hasLocation W43083863142 @default.
• W4308386314 hasLocation W43083863143 @default.

• next