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Drug Resistance: The Role of Sphingolipid Metabolism

Assem Zhakupova1, Adelina Zeinolla1, Kamilya Kokabi1

  • 1Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana 010000, Kazakhstan.

International Journal of Molecular Sciences
|May 7, 2025
PubMed

Insights

Altered sphingolipid metabolism, particularly glucosylceramide synthase, drives cancer drug resistance by promoting cell survival and drug efflux. Targeting these enzymes may restore chemotherapy effectiveness.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Cancer drug resistance significantly challenges therapeutic efficacy.
  • Sphingolipid metabolism dysregulation is an emerging mechanism contributing to cancer drug resistance.
  • Altered sphingolipids in cancer cells promote survival by enabling drug efflux and bypassing apoptosis.

Purpose of the Study:

  • To review the role of sphingolipid metabolism dysregulation in cancer drug resistance.
  • To highlight glucosylceramide synthase (GCS), sphingosine kinase, and acid ceramidase as potential therapeutic targets.

Main Methods:

  • Literature review of studies on sphingolipid metabolism and cancer drug resistance.
  • Analysis of mechanisms linking sphingolipid enzymes to drug efflux and cell survival.
  • Identification of key enzymes involved in sphingolipid-mediated resistance.

Main Results:

  • Upregulated glucosylceramide synthase (GCS) increases ABCB1 gene expression, leading to enhanced drug efflux.
  • Dysregulated sphingolipid metabolism supports cancer cell survival by preventing apoptosis.
  • Specific enzymes like GCS, sphingosine kinase, and acid ceramidase are implicated in resistance.

Conclusions:

  • Targeting enzymes involved in sphingolipid metabolism offers a promising strategy to overcome cancer drug resistance.
  • Modulating sphingolipid pathways could enhance the effectiveness of existing chemotherapeutic agents.
  • Further research into these targets may lead to improved cancer treatment outcomes.
Keywords:
acid ceramidasedrug resistanceglucosylceramide synthasesphingolipid metabolismsphingomyelinasesphingosine kinasesphingosine-1-phosphate

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