Dataset Information

A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.

ABSTRACT: There is growing evidence to support a role for the ceramide-metabolizing enzyme, glucosylceramide synthase (GCS), in resistance to a variety of chemotherapeutic agents. Whether GCS contributes to oxaliplatin resistance in colorectal cancer (CRC) has not yet been determined. We have addressed this potentially important clinical issue by examining GCS function in two panels of oxaliplatin-resistant, isogenic CRC cell lines. Compared to parental cell lines, oxaliplatin-resistant cells have increased expression of GCS protein associated with increased levels of the pro-survival ceramide metabolite, glucosylceramide (GlcCer). Inhibition of GCS expression by RNAi-mediated gene knockdown resulted in a reduction in cellular GlcCer levels, with restored sensitivity to oxaliplatin. Furthermore, oxaliplatin-resistant CRC cells displayed lower ceramide levels both basally and after treatment with oxaliplatin, compared to parental cells. GlcCer, formed by GCS-mediated ceramide glycosylation, is the precursor to a complex array of glycosphingolipids. Differences in cellular levels and species of gangliosides, a family of glycosphingolipids, were also seen between parental and oxaliplatin-resistant CRC cells. Increased Akt activation was also observed in oxaliplatin-resistant CRC cell lines, together with increased expression of the anti-apoptotic protein survivin. Finally, this study shows that GCS protein levels are greatly increased in human CRC specimens, compared to matched, normal colonic mucosa, and that high levels of UGCG gene expression are significantly associated with decreased disease-free survival in colorectal cancer patients. These findings uncover an important cellular role for GCS in oxaliplatin chemosensitivity and may provide a novel cellular target for augmenting chemotherapeutic drug effectiveness in CRC.

SUBMITTER: Madigan JP

PROVIDER: S-EPMC8175058 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundDoctors have always been overwhelmed by tumor drug resistance because it is a major challenge in the clinical treatment of tumors. Cellular senescence has a strong relationship with the development of tumor drug resistance. Herein, we aimed to explore new regulatory factors involved in the aging process of colorectal cancer (CRC) cells and assess the effect of cellular senescence on CRC drug resistance.MethodsGenes associated with cellular senescence for anticipating regulatory factors were first used, and the regulatory molecules of survival significance were then identified based on the results of public database analysis. The effects of E2F translation factor 1 (E2F1) on CRC cell viability, invasion, migration, and cellular senescence processes were assessed through 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-Ethynyl-2'-deoxyuridine (EdU), Transwell, scar repairining, β-galactosidase staining, and cell immunofluorescence assays, respectively. Overexpression or silencing plasmids were used for transfecting HCT116 or OXA-HCT116 to assess the effect of E2F1 on the senescence process and drug resistance in CRC cells.ResultsOn combining the database analysis results with those of our studies, we found that E2F1 was a critical regulator of cellular senescence in CRC. In the in vitro experiments, the E2F1 overexpression significantly stimulated the proliferation, invasion, and migration of CRC cells and even reduced oxaliplatin-induced senescence, further enhancing their resistance to oxaliplatin. Conversely, the tumorigenesis of colorectal cancer was repressed after the suppression of E2F1. Furthermore, CRC cells, which were otherwise resistant to oxaliplatin, also showed senescent phenotypes.ConclusionsOur results suggest that E2F1 suppresses the aging of CRC cells and tumor cells develop resistance to oxaliplatin through high E2F1 expression. Moreover, E2F1 may act as a possible target for oxaliplatin resistance studies.

Dataset Information

A role for ceramide glycosylation in resistance to oxaliplatin in colorectal cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets