铜负金属蛋白，在铜离子的诱导下发现的一种新型程序性细胞死亡，与各种肿瘤的进展和药物耐药有关。Docetaxel在晚期前列腺癌的一线化疗药物中起到重要作用，然而大多数患者最终由于固有或获得性耐药导致前列腺癌的进展。因此，我们在此研究中考察了铜负金属蛋白对前列腺癌对Docetaxel的化疗耐药性的作用。我们用elesclomol-CuCl2和Docetaxel处理前列腺癌细胞系，并进行了细胞增殖检测、集落形成实验、细胞周期流式细胞术、透射电子显微镜和治疗细胞的mTOR信号通路等分析。同时，我们在体内用elesclomol-CuCl2和Docetaxel处理异种移植前列腺癌模型，并在治疗的肿瘤中进行了免疫组织化学和Western blotting分析。我们发现elesclomol-CuCl2能够促进细胞死亡和增强对Docetaxel的化疗敏感性。elesclomol-CuCl2通过诱导铜离子诱导的铜负金属蛋白作用，而不是elesclomol，来诱导细胞死亡和抑制前列腺癌细胞的生长。此外，二氢硫代丙酸脱乙酰转移酶（DLAT）参与了铜负金属蛋白增强对Docetaxel的药物敏感性的抑制。机制上，铜负金属蛋白通过上调DLAT抑制自噬，促进细胞在G2/M期滞留，并通过mTOR信号通路增强了细胞对Docetaxel化疗的敏感性。我们的研究结果表明，铜负金属蛋白调控的DLAT/mTOR通路抑制了自噬，并促进了细胞在G2/M期的滞留，从而增强了对Docetaxel的化疗敏感性。这一发现可能为通过抑制对Docetaxel的化疗耐药性来治疗晚期前列腺癌提供了有效的治疗选择。 © 2023作者。由Wiley Periodicals LLC代表美国实验生物学学会出版的《FASEB期刊》发表

Cuproptosis, 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.© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.