ChaC glutathione specific γ‑glutamylcyclotransferase 1 inhibits cell viability and increases the sensitivity of prostate cancer cells to docetaxel by inducing endoplasmic reticulum stress and ferroptosis

He,Saifei; Zhang,Miao; Ye,Ying; Zhuang,Juhua; Ma,Xing; Song,Yanan; Xia,Wei

doi:10.3892/etm.2021.10429

ChaC glutathione specific γ‑glutamylcyclotransferase 1 inhibits cell viability and increases the sensitivity of prostate cancer cells to docetaxel by inducing endoplasmic reticulum stress and ferroptosis

Authors:
- Saifei He
- Miao Zhang
- Ying Ye
- Juhua Zhuang
- Xing Ma
- Yanan Song
- Wei Xia
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Affiliations: Central Laboratory, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Pudong, Shanghai 200137, P.R. China, Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Pudong, Shanghai 200137, P.R. China
Published online on: July 15, 2021 https://doi.org/10.3892/etm.2021.10429
Article Number: 997
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to determine the effects and mechanism of ChaC glutathione specific γ‑glutamylcyclotransferase 1 (CHAC1) on cell viability and the sensitivity of prostate cancer cells to docetaxel. Compared with non‑tumor human prostate epithelial RWPE‑1 cells, the mRNA and protein levels of CHAC1 significantly decreased in two prostate cancer cell lines, DU145 and 22RV1, as measured by quantitative polymerase chain reaction and western blot analysis (P<0.05). The cell viability and glutathione (GSH) levels were significantly inhibited in prostate cancer cells following overexpression of CHAC1 (P<0.01), while they were significantly increased in DU145 cells transfected with CHAC1 siRNA (P<0.05), but not in 22RV1 cells (P>0.05). The expression levels of several endoplasmic reticulum (ER) stress‑related factors were then measured by western blot analysis. Following transfection with plasmid overexpressing CHAC1, ER markers, BIP and CHOP levels, were significantly upregulated (P<0.01), while GSH co‑treatment decreased this upregulation. In addition, CHAC1 protein levels were significantly upregulated in cells treated with a ferroptosis activator (P<0.05). A liperflo reagent was then used to determine intracellular lipid peroxide levels. The intracellular lipid peroxides levels were significantly increased following CHAC1‑overexpression (P<0.05), while GPX4 protein levels were significantly decreased (P<0.01). The cell viability was significantly inhibited (P<0.001) even with 1 nM docetaxel (DTX) and a plasmid overexpressing CHAC1, while the effect of inhibition was not significant at 1 nM of DTX alone (P>0.05). This inhibition was also eliminated following the addition of a ferroptosis inhibitor. In summary, CHAC1 may inhibit cell viability and increase the sensitivity of prostate cancer cells to DTX. The cellular mechanism may involve the induction of ER stress and ferroptosis. The results of the present study identified a potentially novel therapeutic target for prostate cancer, which may be useful in patients with castration‑resistant prostate cancer.

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