Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate carrier (MPC).
Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate carrier (MPC).
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DOI：
10.1016/j.molmet.2022.101466
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发表时间：
2022-05
影响因子：
8.1
通讯作者：
Wang Z
中科院分区：
文献类型：
--
作者：
Xu H;Liu Z;Gao D;Li P;Shen Y;Sun Y;Xu L;Song N;Wang Y;Zhan M;Gao X;Wang Z
细胞谱系重编程是肿瘤细胞获得耐药性和逃避靶向治疗的主要途径。在癌症中使用有效的靶向治疗导致了高度侵袭性癌症的发展，包括神经内分泌前列腺癌(NEPC)。尽管代谢重编程对肿瘤生长和能量产生至关重要，但在前列腺癌(Pca)中，代谢重编程与导致激素治疗抵抗的谱系分化之间的关系尚未见报道。此外，由于NEPC尚无有效的治疗方法，因此在激素治疗期间逆转这种谱系分化是当务之急。在此，我们首次使用体外和体内的人类PCA模型来研究代谢重编程对雄激素受体(AR)依赖的腺癌向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耐药性和肿瘤的发展。这种表型是由于线粒体丙酮酸载体(MPC)的丧失而实现的，MPC是线粒体丙酮酸内流的大门，MPC的过表达可以逆转这种表型。形态学和细胞学研究也表明，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。它的抑制作用是治疗MPC-LO肿瘤的一种潜在方法。所有这些结果表明，代谢重排可以作为细胞可塑性增加的起始器，从而通过谱系分化导致抗雄激素治疗抵抗。这项研究为治疗诱导的、苯扎鲁胺耐药的NE样前列腺癌提供了一个有效的治疗靶点。线粒体丙酮酸载体(MPC)缺失引起的代谢重排可能是从腺癌到神经内分泌性前列腺癌(NEPC)细胞谱系可塑性增强的始动因素。M2-丙酮酸激酶(PKM2)参与的上皮-间充质转化(EMT)过程介导了这种从雄激素受体(AR)依赖的腺癌到AR非依赖性神经内分泌前列腺癌(NEPC)的谱系转换，这一过程是通过减少线粒体丙酮酸内流而诱导的。线粒体丙酮酸内流可能是NEPC治疗的一个潜在靶点。
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. Metabolic rewiring induced by mitochondrial pyruvate carrier (MPC) loss can act as a starter for increased cellular lineage plasticity from adenocarcinoma into neuroendocrine prostate cancer (NEPC). An M2-pyruvate kinase (PKM2) involved epithelium–mesenchymal transition (EMT) process mediated this lineage switch from the androgen receptor (AR)–dependent adenocarcinoma to AR-independent neuroendocrine prostate cancer (NEPC); this process is induced by the decrease of mitochondria pyruvate influx. Mitochondria pyruvate influx can be a potential target for the NEPC treatment.
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影响因子：
13.8
作者：
Olson KA;Schell JC;Rutter J
通讯作者：
Rutter J
影响因子：
2.8
作者：
Tai, Sheng;Sun, Yin;Squires, Jill M.;Zhang, Hong;Oh, William K.;Liang, Chao-Zhao;Huang, Jiaoti
通讯作者：
Huang, Jiaoti
影响因子：
5.9
作者：
Chen WY;Wen YC;Lin SR;Yeh HL;Jiang KC;Chen WH;Lin YS;Zhang Q;Liew PL;Hsiao M;Huang J;Liu YN
通讯作者：
Liu YN
影响因子：
5.2
作者：
Ruiz-Iglesias A;Mañes S
通讯作者：
Mañes S
DOI：
10.1007/s00018-017-2511-3
发表时间：
2017-08
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Bays JL;DeMali KA
通讯作者：
DeMali KA