Abstract
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.
Highlights
Cancer cells exhibit an altered metabolic profile when compared with normal cells[1]
Combined analysis of the associations between the expression levels of c oxidase subunit 6B2 (COX6B2) and the clinical outcomes of Pancreatic ductal adenocarcinoma (PDAC) revealed that COX6B2 mRNA was significantly increased in poorly differentiated compared with well differentiated PDAC cells (Fig. 1e), and in PDAC tissue with distant metastasis compared with nonmetastatic PDAC tissues (Fig. 1f)
We showed that the COX6B2-regulated function of oxidative phosphorylation function (OXPHOS) was closely associated with the metastatic potential of PDAC cells
Summary
Cancer cells exhibit an altered metabolic profile when compared with normal cells[1]. The Warburg theory on aerobic glycolysis in cancer was advanced during the past decades: an increase in glycolysis flux facilitates glucose utilization in the pentose phosphate pathway (PPP)[4], a Warburg theory that mitochondria respiration becomes impaired during tumorigenesis and suggested that this impairment might promote tumor growth via changing mitochondrial to nuclear signaling pathways[7,8]; it was shown that maintained mitochondrial respiration was essential for tumorigenesis[9] This finding was attributed to the possibility that mitochondrial respiration might support the biosynthesis of metabolites, such as aspartate required for cancer cell proliferation[10].
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