Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
Cancer Translational Medicine Research Center, The Second Hospital, Dalian Medical University, Dalian, China.
J Transl Med. 2023 Aug 16;21(1):547. doi: 10.1186/s12967-023-04403-0.
Resistance to pemetrexed (PEM), a rare chemotherapeutic agent that can efficiently cross the blood-brain barrier, limits the therapeutic efficacy for patients with lung cancer brain metastasis (BM). Aldo-keto reductase family 1 B10 (AKR1B10) was recently found to be elevated in lung cancer BM. The link between AKR1B10 and BM-acquired PEM is unknown.
PEM drug-sensitivity was assessed in the preclinical BM model of PC9 lung adenocarcinoma cells and the BM cells with or without AKR1B10 interference in vitro and in vivo. Metabolic reprogramming of BM attributed to AKR1B10 was identified by chromatography-mass spectrometry (GC-MS) metabolomics, and the mechanism of how AKR1B10 mediates PEM chemoresistance via a way of modified metabolism was revealed by RNA sequencing as well as further molecular biology experimental approaches.
The lung cancer brain metastatic subpopulation cells (PC9-BrM3) exhibited significant resistance to PEM and silencing AKR1B10 in PC9-BrM3 increased the PEM sensitivity in vitro and in vivo. Metabolic profiling revealed that AKR1B10 prominently facilitated the Warburg metabolism characterized by the overproduction of lactate. Glycolysis regulated by AKR1B10 is vital for the resistance to PEM. In mechanism, AKR1B10 promoted glycolysis by regulating the expression of lactate dehydrogenase (LDHA) and the increased lactate, acts as a precursor that stimulates histone lactylation (H4K12la), activated the transcription of CCNB1 and accelerated the DNA replication and cell cycle.
Our finding demonstrates that AKR1B10/glycolysis/H4K12la/CCNB1 promotes acquired PEM chemoresistance in lung cancer BM, providing novel strategies to sensitize PEM response in the treatment of lung cancer patients suffering from BM.
培美曲塞（PEM）是一种罕见的化疗药物，能够有效地穿过血脑屏障，但对肺癌脑转移（BM）患者的治疗效果有限，其耐药性是限制其疗效的主要原因。最近发现醛酮还原酶家族 1 B10（AKR1B10）在肺癌 BM 中升高。AKR1B10 与 BM 获得性 PEM 之间的联系尚不清楚。
在 PC9 肺腺癌细胞的临床前 BM 模型以及体外和体内有或没有 AKR1B10 干扰的 BM 细胞中评估 PEM 药物敏感性。通过色谱-质谱联用（GC-MS）代谢组学鉴定 AKR1B10 引起的 BM 代谢重编程，通过 RNA 测序以及进一步的分子生物学实验方法揭示 AKR1B10 通过修饰代谢介导 PEM 耐药的机制。
肺癌脑转移亚群细胞（PC9-BrM3）对 PEM 表现出显著的耐药性，沉默 PC9-BrM3 中的 AKR1B10 可增加 PEM 在体外和体内的敏感性。代谢谱分析显示，AKR1B10 显著促进了以乳酸过度产生为特征的瓦伯格代谢。AKR1B10 调节的糖酵解对于 PEM 的耐药性至关重要。在机制上，AKR1B10 通过调节乳酸脱氢酶（LDHA）的表达和增加的乳酸来促进糖酵解，作为一种前体，刺激组蛋白乳酰化（H4K12la），激活 CCNB1 的转录，并加速 DNA 复制和细胞周期。
我们的研究结果表明，AKR1B10/糖酵解/H4K12la/CCNB1 促进了肺癌 BM 中获得性 PEM 耐药性，为提高肺癌脑转移患者对 PEM 反应的敏感性提供了新的策略。
