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Targeting UGCG sensitizes AML cells to Venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication

ABSTRACT: UDP-glucose ceramide glucosyltransferase (UGCG) is an enzyme that glycosylates ceramide and blunts its pro-apoptotic activity in cancer cells. Targeting UGCG sensitizes solid cancer cells to chemotherapy. However, whether targeting UGCG can increase the sensitivity of AML cells to Venetoclax remains unclear. Here, we found that the inhibition of UGCG genetically or with its inhibitor Eliglustat efficiently suppressed growth and promoted apoptosis in AML cells. Moreover, Eliglustat in combination with Venetoclax increased apoptosis, reduced AML cell viability, and inhibited AML effectively both for primary AML cells and xenograft models. Mechanistically, the combination induced ceramide accumulation which activated the endoplasmic reticulum (ER) stress-GRP78/PERK/CHOP axis. Interestingly, combinatory treatment activated RAB32, which led to mitochondrial fission through ER-mitochondria communication and DRP1 activation. These findings demonstrate that targeting UGCG in combination with Venetoclax is a new combinatory strategy to treat AML, and provide new insights for ceramide-mediated cell death in anti-cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315549 | GEO | 2026/01/09

REPOSITORIES: GEO

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Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types. Comparison of wildtype mouse liver function versus Ugcg-deficient

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Targeting UGCG sensitizes AML cells to Venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication

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