Inhibition of Ceramide Glycosylation Enhances Cisplatin Sensitivity in Cholangiocarcinoma by Limiting the Activation of the ERK Signaling Pathway

Abstract

Cholangiocarcinoma (CCA) is an aggressive tumor of the biliary epithelium with poor survival that shows limited response to conventional chemotherapy. Increased expression of glucosylceramide synthase (GCS) contributes to drug resistance and the progression of various cancers; the expression profiles of GCS (UGCG) and the genes for glucocerebrosidases 1, 2, and 3 (GBA1, GBA2, and GBA3) were therefore studied in CCA. The biological functions of GCS for cell proliferation and cisplatin sensitivity in CCA were explored. GCS expression was higher in CCA tumor tissues than that of GBA1, GBA2, and GBA3. Verification of GCS expression in 29 paired frozen CCA tissues showed that 8 of 29 cases (27.6%) had high GCS expression. The expression of GCS and GBA2 was induced in CCA cell lines following low-dose cisplatin treatment. Suppression of GCS by either palmitoylamino-3-morpholino-1-propanol (PPMP), GCS knockdown or a combination of the two resulted in reduced cell proliferation. These treatments enhanced the effect of cisplatin-induced CCA cell death, increased the expression of apoptotic proteins and reduced phosphorylation of ERK upon cisplatin treatment. Taken together, inhibition of the GCS increased cisplatin-induced CCA apoptosis via the inhibition of the ERK signaling pathway. Thus, targeting GCS might be a strategy for CCA treatment.

Machine learning to construct sphingolipid metabolism genes signature to characterize the immune landscape and prognosis of patients with uveal melanoma

“…UVM patients were divided into high and low risk groups according to the median risk score, and significant prognostic differences were found between the two groups. In other reports, non-lysosomal β-glucosidase (GBA2) hydrolyzed GlcCer to release ceramide and glucose on the cytoplasmic side of ER and golgi membrane, potentially affecting tumor drug resistance ( 58 , 59 ). Alpha-galactosidase (GLA) has long been considered a key link in Fabry’s disease ( 60 ), but has rarely been studied in tumors, which seems to provide a way to link Fabry’s disease and tumors.…”

Associations between genetic variants in sphingolipid metabolism pathway genes and hepatitis B virus-related hepatocellular carcinoma survival

“…However, since GBA2 can cleave glucosylceramide to produce ceramides, ceramides have been shown to act as tumor suppressors in a variety of tumors ( 35 – 37 ). GBA2 also has been shown to function as a tumor suppressor in melanoma cells and cholangiocarcinoma ( 38 , 39 ). Meanwhile, based on the role of GBA2 in inflammatory response ( 40 ), we analyzed the relationship between GBA2 and immune cell infiltration in the tumor microenvironment, and found that GBA2 was positively correlated with B cells, but negatively correlated with M2 macrophages.…”