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. 2018 Apr;50(4):675-686.
doi: 10.1007/s11255-018-1801-5. Epub 2018 Feb 19.

Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells

Quan Wang  1   2 , Wei-Yang He  1 , Yi-Zhou Zeng  1   2 , Arman Hossain  1   2 , Xin Gou  3
Affiliations

Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells

Quan Wang et al. Int Urol Nephrol. 2018 Apr.

Abstract

Background: This study investigates the docetaxel-resistant mechanism and explores the effect of tea polyphenols (TP) on autophagy and its related mechanism in human castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145.

Methods: Immunofluorescence assay and annexin V-FITC/PI double staining flow cytometry were used to analyze the apoptosis and autophagy of PC3 and DU145 cells. The expression of autophagy-related proteins was detected by western bolt.

Results: Docetaxel could induce autophagy and apoptosis, together with the expression increase in p-JNK, p-Bcl-2 and Beclin1. The level of autophagy was remarkably decreased, but apoptosis was increased after combining with TP. In addition, the expression of p-mTOR was increased after combining with TP.

Conclusion: Docetaxel induces protective autophagy in CRPC cells by JNK pathway activation and then Bcl-2 phosphorylation and Beclin1 dissociation. TP activates mTOR pathway, which ultimately inhibits docetaxel-induced autophagy and improves therapeutic efficacy of docetaxel in CRPC cells.

Keywords: Autophagy; Castration-resistant prostate cancer; Docetaxel resistance; Tea polyphenol.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Docetaxel induces cell apoptosis and autophagy in PC3 and DU145 cells. a PC3 and DU145 cells were treated with various concentrations of Doc for 12 h, and cell extracts were analyzed to determine changes in protein expression by western blot analysis. b PC3 and DU145 cells were treated with Doc (100 ng/ml) for the indicated time. Western blot was used to detect protein expression. c PC3 cells were treated with Doc (100 ng/ml) for 12 h, and LC3 punctate formation was assayed by confocal microscopic analysis. Images are representative of 10 random fields. d PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 12 h with or without CQ pretreatment (10 μM, 30 min). Cell extracts were analyzed for protein expression using western blot analysis. *P < 0.05, **P < 0.01
Fig. 1
Fig. 1
Docetaxel induces cell apoptosis and autophagy in PC3 and DU145 cells. a PC3 and DU145 cells were treated with various concentrations of Doc for 12 h, and cell extracts were analyzed to determine changes in protein expression by western blot analysis. b PC3 and DU145 cells were treated with Doc (100 ng/ml) for the indicated time. Western blot was used to detect protein expression. c PC3 cells were treated with Doc (100 ng/ml) for 12 h, and LC3 punctate formation was assayed by confocal microscopic analysis. Images are representative of 10 random fields. d PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 12 h with or without CQ pretreatment (10 μM, 30 min). Cell extracts were analyzed for protein expression using western blot analysis. *P < 0.05, **P < 0.01
Fig. 2
Fig. 2
Docetaxel induces autophagy by JNK signaling pathway activation in PC3 and DU145 cells. a PC3 cells were cultured in Doc (100 ng/ml) for 12 h with different inhibitor (10 μM, 30 min). Cell extracts were analyzed for protein expression using western blot analysis. b PC3 and DU145 cells were treated with Doc (100 ng/ml) for the indicated time, western blot was used to detect protein expression. c PC3 cells were cultured in Doc (100 ng/ml) for 4 h with or without SP600125 pretreatment (10 μM, 30 min), LC3 punctate formation was assayed by confocal microscopic analysis. Images are representative of 10 random fields. d PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 4 h with or without SP600125 pretreatment (10 μM, 30 min), western blot was used to detect protein expression. *P < 0.05, **P < 0.01
Fig. 2
Fig. 2
Docetaxel induces autophagy by JNK signaling pathway activation in PC3 and DU145 cells. a PC3 cells were cultured in Doc (100 ng/ml) for 12 h with different inhibitor (10 μM, 30 min). Cell extracts were analyzed for protein expression using western blot analysis. b PC3 and DU145 cells were treated with Doc (100 ng/ml) for the indicated time, western blot was used to detect protein expression. c PC3 cells were cultured in Doc (100 ng/ml) for 4 h with or without SP600125 pretreatment (10 μM, 30 min), LC3 punctate formation was assayed by confocal microscopic analysis. Images are representative of 10 random fields. d PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 4 h with or without SP600125 pretreatment (10 μM, 30 min), western blot was used to detect protein expression. *P < 0.05, **P < 0.01
Fig. 3
Fig. 3
TP inhibits docetaxel-induced autophagy and promotes apoptosis in PC3 and DU145 cells. a PC3 cells were cultured in Doc (100 ng/ml) for 12 h with TP (20 μM, 30 min) or 3-MA (10 μM, 30 min) pretreatment, LC3 punctate formation was assayed by confocal microscopic analysis. Images are representative of 10 random fields. b PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 24 h with TP (20 μM, 30 min) or 3-MA (10 μM, 30 min) pretreatment, cell extracts were analyzed for protein expression using western blot analysis. c PC3 cells were cultured in Doc (100 ng/ml) for 24 h with TP (20 μM, 30 min) or 3-MA (10 μM, 30 min) pretreatment, and cell apoptosis was measured by flow cytometry (FCM). The percentages of early and terminal stage apoptotic cells and necrotic cells were calculated. *P < 0.05, **P < 0.01
Fig. 4
Fig. 4
TP inhibits docetaxel-induced autophagy via mTOR signaling pathway activation in PC3 and DU145 cells. a PC3 cells were cultured in Doc (100 ng/ml) for 4 h with or without TP pretreatment (20 μM, 30 min), and western blot was used to detect protein expression. b PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 4 h with a different concentration of TP pretreatment (30 min), and western blot was used to detect protein expression. c PC3 and DU145 cells were cultured in Doc (100 ng/ml) for 4 h with or without TP (20 μM, 30 min) or RAPA (100 nM, 30 min), and western blot was used to detect protein expression. *P < 0.05, **P < 0.01
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