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Updated: Sep 11, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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DGAT1 Inhibition Enhances Olaparib-Induced Lipotoxic Apoptosis in Metastatic Castration-Resistant Prostate Cancer.

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FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
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Combining a DGAT1 inhibitor with Olaparib overcomes resistance in prostate cancer by disrupting lipid storage, increasing cell death, and enhancing anti-cancer effects.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) shows limited durable responses to poly (ADP-ribose) polymerase (PARP) inhibitors like Olaparib.
  • Resistance to Olaparib is linked to autophagy-induced free fatty acid (FFA) availability and lipid droplet (LD) formation via diacylglycerol O-acyltransferase 1 (DGAT1).

Purpose of the Study:

  • To investigate if inhibiting DGAT1 can disrupt cancer cell protective mechanisms against Olaparib.
  • To evaluate the combined effect of a DGAT1 inhibitor (DGAT1i) and Olaparib on lipid metabolism, oxidative stress, and cell death in prostate cancer cells.

Main Methods:

  • In vitro evaluation of prostate cancer cell lines treated with Olaparib and a DGAT1 inhibitor.
  • Assessment of lipid droplet dynamics, mitochondrial integrity, FFA accumulation, oxidative stress, and apoptosis.
  • Analysis of protein expression related to autophagy, lipogenesis, and apoptosis.

Main Results:

  • DGAT1 inhibition potentiated Olaparib's anti-proliferative effects.
  • Combination treatment reduced LD formation, increased FFA accumulation and lipotoxicity, and elevated oxidative stress and mitochondrial damage.
  • Enhanced programmed cell death was observed with the dual treatment.

Conclusions:

  • Inhibiting DGAT1 disrupts lipid droplet biogenesis, enhancing Olaparib's efficacy and potentially overcoming resistance in prostate cancer.
  • This dual-targeting strategy induces lipotoxicity and oxidative stress, leading to cancer cell death.
  • The findings support DGAT1 inhibition as a novel therapeutic approach to improve Olaparib treatment outcomes in mCRPC.