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Glucosylceramide Synthase, a Key Enzyme in Sphingolipid Metabolism, Regulates Expression of Genes Accounting for

Md Saqline Mostaq1, Lin Kang2,3, Gauri A Patwardhan1

  • 1School of Basic Pharmaceutical and Toxicological Sciences, University of Louisiana at Monroe, Monroe, LA 71201, USA.

International Journal of Molecular Sciences
|June 13, 2025
PubMed

Insights

Enhanced ceramide glycosylation promotes cancer drug resistance and metastasis by altering gene expression. Silencing glucosylceramide synthase (GCS) restores sensitivity to chemotherapy, indicating GCS as a therapeutic target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Cancer drug resistance and metastasis are linked to altered gene expression.
  • Enhanced ceramide glycosylation, via glucosylceramide synthase (GCS), confers drug resistance and enriches cancer stem cells.
  • p53 mutations are common in ovarian cancers and can promote tumor progression.

Purpose of the Study:

  • To characterize GCS-responsive genes in ovarian cancer cells under chemotherapy.
  • To investigate the role of GCS in dactinomycin resistance and cancer stem cell enrichment.
  • To explore the therapeutic potential of targeting GCS in ovarian cancer.

Main Methods:

  • Integrated gene expression assessments (microarray analysis).
  • Silencing GCS expression in NCI/ADR-RES ovarian cancer cells.
  • Genomic analyses of ovarian cancer data from The Cancer Genome Atlas (TCGA).

Main Results:

  • Silencing GCS restored sensitivity to dactinomycin-induced apoptosis in resistant cells.
  • Elevated GCS expression correlated with altered expression of 41 genes, including ABCB1, FGF2, and IL6.
  • Altered gene expression was associated with apoptosis resistance, cancer stem cell enrichment, and cancer progression.

Conclusions:

  • Altered ceramide glycosylation modulates GCS-responsive genes, impacting cancer cell behavior under chemotherapy.
  • Targeting GCS may overcome drug resistance and inhibit metastasis in ovarian cancer.
  • Findings were validated using TCGA data and studies on platinum-based chemotherapy resistance.
Keywords:
apoptosisdactinomycingene mutationglucosylceramide synthasemicroarrayovarian cancerp53 tumor suppressor

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