Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

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Τετάρτη 4 Αυγούστου 2021

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

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Exp Ther Med. 2021 Sep;22(3):997. doi: 10.3892/etm.2021.10429. Epub 2021 Jul 15.

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 measure d 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 c ells 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.

PMID:34345279 | PMC:PMC8311285 | DOI:10.3892/etm.2021.10429

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