Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells

Shao, Z. C.; Zhu, B. H.; Huang, A. F.; Su, M. Q.; An, L. J.; Wu, Z. P.; Jiang, Y. J.; Guo, H.; Han, X.-Q.; Liu, Chi-Ming

doi:10.14712/fb2022068020059

Folia Biologica > Archive > 2022, Vol. 68 > Issue 2 > Docosahexaenoic Acid Reverses…

Fol. Biol. 2022, 68, 59-71

https://doi.org/10.14712/fb2022068020059

Docosahexaenoic Acid Reverses Epithelial-Mesenchymal Transition and Drug Resistance by Impairing the PI3K/AKT/Nrf2/GPX4 Signalling Pathway in Docetaxel-Resistant PC3 Prostate Cancer Cells

Z. C. Shao^1,2, B. H. Zhu², A. F. Huang², M. Q. Su^1,2, L. J. An^1,2, Z. P. Wu^2,3, Y. J. Jiang², H. Guo², X.-Q. Han², Chi-Ming Liu²

¹College of Chemistry and Bio-engineering, Yichun University, Yuanzhou District, Yichun 336000, Jiangxi Province, China
²School of Medicine, Yichun University, Yuanzhou District, Yichun 336000, Jiangxi Province, China
³School of Aesthetic Medicine, Yuanzhou District, Yichun 336000, Jiangxi Province, China

Received November 2021
Accepted April 2022

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase-3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT/Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

Keywords

docosahexaenoic acid, drug resistance, ferroptosis, GPX4, autophagy, prostate.

Funding

The present study was supported by “Yichun University Local Development Research Center” (Grant No. DF2019002), “PhD research foundation of Yichun University” (Grant No. 211-3360118006), and “Undergraduate Innovation and Entrepreneurship Training Program” (Grant No. 201910417007).