Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with poor prognosis due to its high metastatic potential, however, the role of metabolic reprogramming in the metastasis of PDAC cell is not known. Here, we report that COX6B2 drive metastasis but not cancer cell proliferation in PDAC by enhancing oxidative phosphorylation function (OXPHOS). Transcriptome and clinical analyses revealed that cytochrome c oxidase subunit 6B2 (COX6B2) positively associated with metastasis of PDAC cells. Knockdown of COX6B2 in PDAC cells tuned down the assembly of complex IV and downregulated the function of OXPHOS, whereas re-expression of COX6B2 restored the function of OXPHOS and metastatic potential. Mechanistically, COX6B2 upregulated OXPHOS function to active purinergic receptor pathway for the metastasis of PDAC cells. Notably, the metastatic potential in PDAC could be reversely regulated by metformin, a drug was found accelerating the degradation of COX6B2 mRNA in this study. Collectively, our findings indicated that a complex metabolic control mechanism might be involved in achieving the balance of metabolic requirements for both growth and metastasis in PDAC, and regulation of the expression of COX6B2 could potentially encompass one of the targets.

中文翻译：

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COX6B2驱动代谢重编程向氧化磷酸化，以促进胰腺导管癌细胞的转移。

胰腺导管腺癌（PDAC）由于具有高转移潜力，因此是一种预后较差的侵袭性癌症，但是，代谢重编程在PDAC细胞转移中的作用尚不清楚。在这里，我们报告说COX6B2通过增强氧化磷酸化功能（OXPHOS）来驱动PDAC中的转移而不是癌细胞增殖。转录组和临床分析表明，细胞色素C氧化酶亚基6B2（COX6B2）与PDAC细胞的转移正相关。降低PDAC细胞中COX6B2的表达可降低复合物IV的装配并下调OXPHOS的功能，而COX6B2的重新表达可恢复OXPHOS的功能和转移潜力。从机理上讲，COX6B2上调了OXPHOS的功能，使嘌呤能受体途径活跃于PDAC细胞的转移。值得注意的是 二甲双胍可逆转PDAC中的转移潜能，本研究发现一种药物可加速COX6B2 mRNA的降解。总的来说，我们的发现表明，复杂的代谢控制机制可能参与实现PDAC生长和转移的代谢需求平衡，并且对COX6B2表达的调节可能涵盖了其中一个靶标。