Language

English

Publication Date

4-1-2024

Journal

World Journal of Clinical Oncology

DOI

10.14740/wjon1768

PMID

38545484

PMCID

PMC10965266

PubMedCentral® Posted Date

3-21-2024

PubMedCentral® Full Text Version

Post-print

Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer resistant to current therapies, including oxaliplatin (Oxa). Growing evidence supports the ability of cancers to harness sphingolipid metabolism for survival. Sphingosine-1-phosphate (S1P) is an anti-apoptotic, pro-survival mediator that can influence cellular functions such as endoplasmic reticulum (ER) stress. We hypothesize that PDAC drives dysregulated sphingolipid metabolism and that S1P inhibition can enhance ER stress to improve therapeutic response to Oxa in PDAC.

METHODS: RNA sequencing data of sphingolipid mediators from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) datasets were analyzed. Murine and human PDAC cell lines were treated with small interfering RNA (siRNA) against sphingosine kinase-2 (SPHK2) or ABC294640 (ABC) and incubated with combinations of vehicle control or Oxa. In an orthotopic syngeneic KPC PDAC model, tumors were treated with either vehicle control, Oxa, ABC, or combination therapy.

RESULTS: RNA sequencing analysis revealed multiple significantly differentially expressed sphingolipid mediators (P < 0.05).

CONCLUSIONS: Our evidence suggests that sphingolipid metabolism is dysregulated in PDAC. Furthermore, S1P inhibition can sensitize PDAC to Oxa therapy through increasing ER stress and can potentiate ICD induction. This highlights a potential therapeutic target for chemosensitizing PDAC as well as an adjunct for future chemoimmunotherapy strategies.

Keywords

Sphingosine-1-phosphate, Pancreatic ductal adenocarcinoma, Oxaliplatin, Endoplasmic reticulum stress

Published Open-Access

yes

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