Abstract
PGC1α acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1α on cholangiocarcinoma (CCA). Here we showed that PGC1α overexpression had no impact on CCA growth despite the decreased expression of PGC1α in CCA compared with adjacent normal tissue. Instead, PGC1α overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1α reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. On the one hand, enhanced mitochondrial oxidation metabolism correlated with elevated reactive oxygen species (ROS) production; on the other hand, increased PGC1α expression upregulated the expression levels of mRNA for several ROS-detoxifying enzymes. To this end, the ROS levels, which were elevated but below a critical threshold, did not inhibit CCA cells proliferation. And the moderately increased ROS facilitated metastatic dissemination of CCA cells, which can be abrogated by antioxidants. Our study suggests the potential utility of developing the PGC1α-targeted therapies or blocking PGC1α signaling axis for inhibiting CCA metastasis.
Highlights
The overall incidence of cholangiocarcinoma (CCA) appears to have increased[1,2], and cumulative CCA mortality has risen by 39% because of increased disease incidence[3]
We found that knockdown of pyruvate dehydrogenase E1 alpha 1 subunit (PDHA1) and mitochondrial pyruvate carrier 1 (MPC1) reversed the avidity of PGC1α overexpression cells for oxidative phosphorylation (OXPHOS) (Fig. 6e) and blocked tumor cells migration and invasion mediated by PGC1α (Fig. 6f and Supplementary Figure 5B)
Our data showed that the PGC1α expression was reduced in CCA compared with noncancerous tissue
Summary
The overall incidence of cholangiocarcinoma (CCA) appears to have increased[1,2], and cumulative CCA mortality has risen by 39% because of increased disease incidence[3]. The difficulty in diagnosing CCA in the early. There is an urgent need to understand the molecular mechanism underlying CCA progression. Metabolic reprogramming is firmly established as “Achilles’ heel” of cancer cells[4]. Tumors are even regarded as a metabolic disease[5]. The best characterized energy metabolism modification in cancer cells is the Warburg effect, wherein tumor cells oxidize a reduced fraction of the pyruvate generated from glycolysis. It is the long-term correlation of cancer metabolism with aerobic glycolysis that strikingly belies the crucial role of mitochondria in cancer cells[6].
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