Department of Urology, Shanghai Ninth People's Hospital, Shanghai, China.
Shanghai Key Lab of Cell Engineering, Shanghai, China; Research Center of Developmental Biology, Department of Histology and Embryology, College of Basic Medicine, Naval Medical University, Shanghai, China.
Mol Metab. 2022 May;59:101466. doi: 10.1016/j.molmet.2022.101466. Epub 2022 Feb 25.
Cell lineage reprogramming is the main approach for cancer cells to acquire drug resistance and escape targeted therapy. The use of potent targeted therapies in cancers has led to the development of highly aggressive carcinoma, including neuroendocrine prostate cancer (NEPC). Although metabolic reprogramming has been reported to be essential for tumor growth and energy production, the relationship between metabolic reprogramming and lineage differentiation which can cause hormone therapy resistance has never been reported in prostate cancer (PCa). Moreover, as there is still no efficient therapy for NEPC, it is urgent to reverse this lineage differentiation during the hormone therapy. Here for the first time, we used in vitro and in vivo human PCa models to study the effect of metabolic reprogramming on the lineage differentiation from the androgen receptor (AR)-dependent adenocarcinoma to AR-independent NEPC. This lineage differentiation leads to antiandrogen drug resistance and tumor development. This phenotype is enabled by the loss of mitochondrial pyruvate carrier (MPC), the gate for mitochondrial pyruvate influx, and can be reversed by MPC overexpression. Morphologic and cellular studies also demonstrate that the pyruvate kinase M2 (PKM2) involved epithelium-mesenchymal transition process mediated this lineage alteration. Its inhibition is a potential treatment for MPC-lo tumors. All of these results suggest that metabolic rewiring can act as a starter for increased cellular plasticity which leads to antiandrogen therapy resistance through lineage differentiation. This study provides us with a potent treatment target for therapy-induced, enzalutamide-resistant NE-like prostate cancer.
细胞谱系重编程是癌细胞获得耐药性并逃避靶向治疗的主要途径。在癌症中使用强效的靶向治疗方法导致了高度侵袭性癌的发展，包括神经内分泌前列腺癌（NEPC）。尽管代谢重编程已被报道对肿瘤生长和能量产生至关重要，但代谢重编程与导致激素治疗耐药的谱系分化之间的关系在前列腺癌（PCa）中从未被报道过。此外，由于目前仍然没有针对 NEPC 的有效治疗方法，因此迫切需要在激素治疗期间逆转这种谱系分化。在这里，我们首次使用体外和体内人 PCa 模型来研究代谢重编程对从雄激素受体（AR）依赖性腺癌到 AR 非依赖性 NEPC 的谱系分化的影响。这种谱系分化导致抗雄激素药物耐药和肿瘤发展。这种表型是由线粒体丙酮酸载体（MPC）的缺失引起的，MPC 是线粒体丙酮酸流入的门控，并且可以通过 MPC 的过表达逆转。形态和细胞研究还表明，参与上皮-间充质转化过程的丙酮酸激酶 M2（PKM2）介导了这种谱系改变。其抑制可能是治疗 MPC-lo 肿瘤的一种潜在方法。所有这些结果表明，代谢重编程可以作为增加细胞可塑性的启动子，通过谱系分化导致抗雄激素治疗耐药。这项研究为我们提供了一种针对治疗诱导的、恩扎鲁胺耐药的 NE 样前列腺癌的有效治疗靶点。
