Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer

Author:

Wen Hongzhuang1ORCID,Qu Changbao1ORCID,Wang Zhu1ORCID,Gao Haitao1ORCID,Liu Wuyao1ORCID,Wang Hu1ORCID,Sun Hao1ORCID,Gu Junfei1ORCID,Yang Zhan12ORCID,Wang Xiaolu1ORCID

Affiliation:

1. Department of Urology The Second Hospital of Hebei Medical University Shijiazhuang China

2. Molecular Biology Laboratory, Talent and Academic Exchange Center The Second Hospital of Hebei Medical University Shijiazhuang China

Abstract

AbstractCuproptosis, a newly discovered programmed cell death induced by copper ions, is associated with the progression and drug resistance of various tumors. Docetaxel plays a vital role as a first‐line chemotherapeutic agent for advanced prostate cancer; however, most patients end up with prostate cancer progression because of inherent or acquired resistance. Herein, we examined the role of cuproptosis in the chemotherapeutic resistance of prostate cancer to docetaxel. We treated prostate cancer cell lines with elesclomol–CuCl2, as well as with docetaxel. We performed analyses of CCK8, colony formation tests, cell cycle flow assay, transmission electron microscopy, and mTOR signaling in treated cells, and treated a xenograft prostate cancer model with elesclomol–CuCl2 and docetaxel in vivo, and performed immunohistochemistry and Western blotting analysis in treated tumors. We found that elesclomol–CuCl2 could promote cell death and enhance chemosensitivity to docetaxel. Elesclomol–CuCl2 induced cell death and inhibited the growth of prostate cancer cells relying on copper ions‐induced cuproptosis, not elesclomol. In addition, dihydrolipoamide S‐acetyltransferase (DLAT) was involved in cuproptosis‐enhanced drug sensitivity to docetaxel. Mechanistically, upregulated DLAT by cuproptosis inhibited autophagy, promoted G2/M phase retention of cells, and enhanced the sensitivity to docetaxel chemotherapy in vitro and in vivo via the mTOR signaling pathway. Our findings demonstrated that the cuproptosis‐regulated DLAT/mTOR pathway inhibited autophagy and promoted cells in G2/M phase retention, thus enhancing the chemosensitivity to docetaxel. This discovery may provide an effective therapeutic option for treating advanced prostate cancer by inhibiting the chemotherapeutic resistance to docetaxel.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Genetics,Molecular Biology,Biochemistry,Biotechnology

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