Antidiabetic drug metformin suppresses tumorigenesis through inhibition of mevalonate pathway enzyme HMGCS1

Targeting the sphingolipid rheostat in IDH1mutglioma alters cholesterol homeostasis and triggers apoptosis via membrane degradation

“…LXR signaling can modulate cholesterol homeostasis by activating expression genes, ABCA1 and ABCG1 involved in reverse cholesterol transport; MYLIP that activate ubiquitinated digestion of influx protein LDLR; and suppression of the cascade genes involved in cholesterol and precursor biosynthesis (Rong et al, 2013;Tarling et al, 2011;Yvan-Charvet et al, 2010;Zelcer et al, 2009;Zhu et al, 2012). Complementary to transcriptomic RNA expression data, immunoblot analysis also demonstrated a decline for enzymes involved (HMGCR and HMGCS) in the rate-limiting entry for cholesterol, sterol, and isoprenoid biosynthesis (Chen et al, 2022;DeBose-Boyd, 2008;Yeh et al, 2018).…”

“…In previous studies, the expression of catalytic enzymes (HMGCR and lanosterol synthase, LSS) involved in sterol and Cholesterol biosynthesis was positively attributed to GBM malignancy (Phillips et al, 2019; Qiu et al, 2016). Moreover, HMGCR has also become the focus point in tumor progression research due to its pivotal function in the production of precursors for cholesterol and other sterol biosynthesis (Chen et al, 2022; Qiu et al, 2016; H. yan Wang et al, 2022; Zhang et al, 2019).…”

“…Cholesterol levels can suspend the expression of catalytic enzymes responsible for isoprenoid precursor, sterol, and cholesterol biosynthesis, which is initialized by hydroxymethylglutaryl-CoA synthase (HGMCS) activity. In relation, HMGCS forms intermediate HMG-CoA by condensing acetyl-CoA and acetoacetyl-CoA, typically supplied by β-oxidation of fatty acids ((Chen et al, 2022). The rate-limiting NADH-dependent HMG-CoA reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonate, the essential precursor for isoprenoid, sterol, and cholesterol biosynthesis (DeBose-Boyd, 2008; H. yan Wang et al, 2022; Yeh et al, 2018).…”

“…Cholesterol and sterol feedback can also trigger the binding of LXR-mediated Insulin-induced gene 1 (Insig-1) to HMGCR which recruits gp78 ubiquitin ligase to accelerate ubiquitination and proteolytic degradation of HMGCR in the ER (DeBose-Boyd, 2008; Feramisco et al, 2004; Sever et al, 2003). Interestingly, HMGCS and HMGCR have also become a recent focus in the development of anti-cancer combination treatments for their crucial role in tumor progression (Chen et al, 2022; H. yan Wang et al, 2022; Zhang et al, 2019).…”

Host Expression Profiling From Diagnostic Coronavirus Disease 2019 Swabs Associates Upper Respiratory Tract Immune Responses With Radiologic Lung Pathology and Clinical Severity

“…Thus, upregulation of HMGCS1 may contribute to viral dissemination, resulting in inflammation and disease severity, and may partially explain the observed lung scores in our ICU patients. As the HMGCS1 axis is also implicated in “stemness” properties related to cancer stem cells, one may also postulate whether this biomarker reflects a level of epithelial damage and initiation of regeneration programs [ 22 , 28 ].…”