Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance
Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance
复制标题
代谢酶 PDK3 与转录因子 HSF1 形成正反馈环以驱动化疗耐药
DOI：
10.7150/thno.31301
复制
发表时间：
2019
期刊：
影响因子：
12.4
通讯作者：
Jin Hongchuan
中科院分区：
文献类型：
--
作者：
Xu Jinye;Shi Qiqi;Xu Wenxia;Zhou Qiyin;Shi Rongkai;Ma Yanning;Chen Dingwei;Zhu Liyuan;Feng Lifeng;Cheng Alfred Sze-Lok;Morrison Helen;Wang Xian;Jin Hongchuan
背景和目标：代谢失调在癌症的发生和发展中起着重要作用，而其潜在机制在很大程度上仍不清楚。本研究旨在探讨糖酵解在胃癌化疗耐药中的调控作用及其相关性。研究方法：通过代谢谱、微阵列基因表达、PCR或蛋白质印迹来确定化学抗性和化学敏感性癌细胞之间的生化差异。通过存活率、凋亡和裸鼠实验分析癌细胞在体外或体内的生长。免疫沉淀用于探索蛋白质与其他蛋白质或DNA的相互作用。结果如下：通过代谢和基因表达谱分析，我们发现丙酮酸脱氢酶激酶3（PDK3）在耐药癌细胞中高表达，以促进糖酵解。它的遗传或化学抑制逆转了体外和体内的耐药性。它的转录受转录因子HSF 1（热休克因子1）的调控。有趣的是，PDK3可以定位在细胞核中，并与HSF 1相互作用，破坏其被GSK 3 β磷酸化。由于HSF1以磷酸化依赖的方式进行FBXW7催化的多聚泛素化，PDK3阻止HSF1被蛋白酶体降解。因此，代谢酶PDK3和转录因子HSF1形成正反馈环以促进糖酵解。因此，抑制HSF 1会削弱体外和体内糖酵解的增强并逆转化疗耐药性。结论：PDK3与HSF 1形成正反馈环，在化疗耐药中驱动糖酵解。靶向这种线粒体通讯可能代表了一种克服化疗耐药性的新方法。
Background & Aims: Dysregulation of metabolism plays an important role in the development and progression of cancers, while the underlying mechanisms remain largely unknown. This study aims to explore the regulation and relevance of glycolysis in chemoresistance of gastric cancer. Methods: Biochemical differences between chemoresistant and chemosensitive cancer cells were determined by metabolism profiling, microarray gene expression, PCR or western blotting. Cancer cell growth in vitro or in vivo were analyzed by viability, apoptosis and nude mice assay. Immunoprecipation was used to explore the interaction of proteins with other proteins or DNAs. Results: By metabolic and gene expression profiling, we found that pyruvate dehydrogenase kinase 3 (PDK3) was highly expressed to promote glycolysis in chemoresistant cancer cells. Its genetic or chemical inhibition reverted chemoresistance in vitro and in vivo. It was transcriptionally regulated by transcription factor HSF1 (Heat shock factor 1). Interestingly, PDK3 can localize in the nucleus and interact with HSF1 to disrupt its phosphorylation by GSK3β. Since HSF1 was subjected to FBXW7-catalyzed polyubiquitination in a phosphorylation-dependent manner, PDK3 prevented HSF1 from proteasomal degradation. Thus, metabolic enzyme PDK3 and transcription factor HSF1 forms a positive feedback loop to promote glycolysis. As a result, inhibition of HSF1 impaired enhanced glycolysis and reverted chemoresistance both in vitro and in vivo. Conclusions: PDK3 forms a positive feedback loop with HSF1 to drive glycolysis in chemoresistance. Targeting this mitonuclear communication may represent a novel approach to overcome chemoresistance.