Cancer Letters

Cancer Letters

Volume 416, 1 March 2018, Pages 24-30
Cancer Letters

Original Articles
Docetaxel-mediated autophagy promotes chemoresistance in castration-resistant prostate cancer cells by inhibiting STAT3

https://doi.org/10.1016/j.canlet.2017.12.013Get rights and content

Highlights

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    Docetaxel induces autophagy in castration-resistant prostate cancer cells.

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    Docetaxel activates autophagy by Beclin1-Vps34-Atg14 complex formation.

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    STAT3 signaling negatively regulates docetaxel-induced autophagy.

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    Inhibiting autophagy enhances sensitivity to chemotherapy in castration-resistant prostate cancer cells.

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    STAT3 influences the chemosensitivity in castration resistant prostate cancer cells.

Abstract

Signal transducer and activator of transcription (STAT)3 expression is correlated with neoplasm growth, metastasis, and prognosis; it has also been implicated in the regulation of autophagy, which may in turn contribute to tumor chemoresistance. However, it is unknown whether STAT3 is involved in cancer cell survival in response to chemotherapy. In this study, we show that autophagy is triggered during chemotherapy and that inhibiting autophagy increased chemosensitivity of castration-resistant prostate cancer (CRPC) cells. Meanwhile, docetaxel induced autophagy was inhibited by STAT3 activation, which increased mitochondrial damage and decreased CRPC cell viability. These results suggest that STAT3 contributes to CRPC cell survival and chemoresistance by modulating autophagy.

Introduction

Prostate cancer is the second most lethal malignancy in males worldwide [1], with the incidence surging in China in recent years [2]. Androgen deprivation therapy is one of the most effective treatments for prostate cancer, but most patients exhibit resistance after 14–30 months of therapy and eventually develop castration-resistant prostate cancer (CRPC) [3], which is difficult to treat. Clarifying the mechanism of chemoresistance in CRPC can provide a basis for new treatment approaches.

Autophagy is a highly conserved lysosome-associated pathway that maintains cellular homeostasis and promotes cell survival under conditions of stress [4]. In this process, degraded organelles and cytoplasmic proteins are engulfed by double-membrane vesicles known as autophagosomes that then fuse with lysosomes. The content of the resultant autolysosomes are broken down to amino acids and other precursors of anabolism. In most cells, autophagy occurs at low levels [5], and its perturbation can lead to various diseases including cancer, neurodegeneration, and heart disease [6]. It has also been suggested that autophagy contributes to the resistance of tumors to radiotherapy and chemotherapy [7].

The Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling pathway is activated by cytokines and is involved in many biological processes including cell proliferation, apoptosis, and immune regulation [8,9]. STAT3 is aberrantly expressed in many tumors, and its activation affects tumor angiogenesis and growth and cell apoptosis [10,11]. It was previously reported that STAT3 can regulate autophagy [12], however, its role in chemoresistance has never been reported.

We addressed this in the present study, by investigating the relationship between STAT3 and autophagy in CRPC cells. The results indicate that STAT3 contributes to CRPC cell survival and chemoresistance via modulation of autophagy.

Section snippets

Cell culture and treatment

PC3 and DU145 human CRPC cell lines were obtained from the Central Laboratory of Shanghai Tenth People's Hospital (Shanghai, China) and were cultured in Roswell Park Memorial Institute-1640 medium (Gibco; Grand Island, NY, USA) supplemented with 10% fetal bovine serum (Shanghai Excell Biology, Shanghai, China), 100 U/ml penicillin and 100 mg/ml streptomycin in a humidified incubator with 5% CO2 at 37 °C. Cells were treated with culture medium containing 10 nM docetaxel (Sanofi-Aventis

Docetaxel induces autophagy in CRPC cells

To investigate the role of autophagy during chemotherapy, CRPC cell lines were transfected with GFP-LC3 plasmid and then cultured for 24 h in docetaxel. Cell nuclei were stained with DAPI. Cells cultured in docetaxel showed a higher percentage of GFP punctate, whereas in untreated cells the GFP signal was diffuse (Fig. 1A and B). An electron microscopy analysis revealed an increased number of autophagosomes in docetaxel-treated CRPC cells (Fig. 1C). Consistent with these observations,

Discussion

Autophagy is an essential catabolic reactions in cells in response to stimulation or stress [26] and is implicated in chemoresistance; inhibititing autophagy has been shown to enhance chemosensitivity in cancer cells [[27], [28], [29]], although the exact mechanism has not been elucidated.

Under certain conditions-particularly when apoptosis is inhibited-autophagy contributes to chemotherapy-induced cell death [30], although the distinction between ‘autophagic cell death’ and ‘autophagy with

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

This project was supported by the National Natural Science Foundation of China (Grant NO. 81372749, 81772905, 81702311); Shanghai Committee of Science and Technology, China (Grant NO. 11411950602); Shanghai Health System Advanced Technology Promotion Project, China (Grant NO. 2013SY046); and the Fundamental Research Funds for the Central Universities, China (Grant NO. 1501219146).

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