PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect

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.

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

“…Despite these data showing a marked dependence of on Warburg metabolism, Dan Li et al, demonstrated that PGC1α overexpression reversed the effect and increased pyruvate flux into the mitochondria by up-regulating both pyruvate dehydrogenase E1 alpha 1 Subunit and mitochondrial pyruvate carrier 1 expression. These events induced mitochondrial biogenesis and the metabolic switch to oxidative phosphorylation (OXPHOS), finally facilitating CCA cells migration and invasion [49]. Collectively all these data suggest a great ability of CCA cells to shift between different metabolic pathways in order to adapt to environmental changes and to survive.…”

“…Promotion of CCA metastasis both in vitro and in vivo. [49] Sirt1/FOXO1 stimulation Involvement in autophagy and mitochondrial dysfunction in CCA cells. [50] Lipid metabolism FASN down-regulation In human and mouse iCCA tissues FASN expression was down-regulated respect to non-tumor adjacent tissues.…”

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…Nevertheless, excessive PGC-1α activation may alter mitochondrial homeostasis as observed in podocytes [178], suggesting that it is important to establish the optimal therapeutic window for PGC-1α activation. In addition, PGC-1α over activation could be deleterious in cancer [196,197], thus therapeutic strategies to preserve PGC-1α function should ideally be specific of the tissue/s in which PGC-1α downregulation is pathogenic.…”

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

“…In contrast to COUP-TFII, peroxisome proliferator-activated receptor-gamma co-activator (PGC)-1 alpha (PGC-1α) was found to increase expression of MPC1 in human renal cell carcinoma [28] and cholangiocarcinoma [29]. Overexpression of PGC-1α strongly stimulated MPC1 transcription through binding to the MPC1 promoter, while depletion of PGC-1α by small interfering RNA (siRNA) suppressed MPC1 expression.…”