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Roles of PPAR activation in cancer therapeutic resistance: Implications for combination therapy and drug development

Yanxia Zhang1, Bin Xiao2, Yunduo Liu2

  • 1School of Medicine, The South China University of Technology, Guangzhou, 510006, China; Department of Laboratory Medicine, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China.

European Journal of Pharmacology
|December 24, 2023
PubMed

Insights

Excessively activated Peroxisome proliferator-activated receptors (PPARs) promote cancer therapeutic resistance by altering cell metabolism and promoting survival. PPAR antagonists show promise in overcoming this resistance for better cancer management.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Therapeutic resistance is a significant challenge in cancer treatment.
  • Peroxisome proliferator-activated receptors (PPARs) are key regulators of cellular processes with complex roles in cancer.
  • Emerging evidence links PPARs to resistance against various anti-cancer therapies.

Purpose of the Study:

  • To review the role of activated PPARs in promoting resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy.
  • To elucidate the mechanisms by which PPARs contribute to therapeutic resistance and multidrug resistance in cancer.
  • To discuss the potential of PPAR antagonists in overcoming cancer resistance.

Main Methods:

  • Literature review of studies investigating PPARs and cancer therapeutic resistance.
  • Analysis of mechanisms including metabolic reprogramming, anti-apoptosis, proliferation, and immunosuppression.
  • Examination of PPAR-mediated multidrug resistance pathways like drug efflux and cancer stem cell maintenance.

Main Results:

  • Activated PPARs contribute to resistance through metabolic reprogramming, enhanced antioxidant defense, anti-apoptotic signaling, and promotion of proliferation.
  • PPARs induce an immunosuppressive tumor microenvironment, hindering immunotherapy.
  • PPARs facilitate multidrug resistance via drug efflux, epithelial-to-mesenchymal transition, and cancer stem cell phenotypes.

Conclusions:

  • Overactivated PPARs are implicated in resistance to diverse cancer treatments.
  • Targeting PPARs with antagonists may offer a strategy to reverse therapeutic resistance.
  • Further research and clinical translation of PPAR-targeting strategies are warranted for improved cancer management.
Keywords:
Cancer therapeutic resistanceChemotherapyImmunotherapyPeroxisome proliferator-activated receptorsRadiotherapyTargeted therapy

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