Mitochondrial Retrograde Signaling Mediated by UCP2 Inhibits Cancer Cell Proliferation and Tumorigenesis

Abstract

Cancer cells tilt their energy production away from oxidative phosphorylation (OXPHOS) toward glycolysis during malignant progression, even when aerobic metabolism is available. Reversing this phenomenon, known as the Warburg effect, may offer a generalized anticancer strategy. In this study, we show that overexpression of the mitochondrial membrane transport protein UCP2 in cancer cells is sufficient to restore a balance toward oxidative phosphorylation and to repress malignant phenotypes. Altered expression of glycolytic and oxidative enzymes mediated the effects of this metabolic shift. Notably, UCP2 overexpression increased signaling from the master energy-regulating kinase, adenosine monophosphate-activated protein kinase, while downregulating expression of hypoxia-induced factor. In support of recent new evidence about UCP2 function, we found that UCP2 did not function in this setting as a membrane potential uncoupling protein, but instead acted to control routing of mitochondria substrates. Taken together, our results define a strategy to reorient mitochondrial function in cancer cells toward OXPHOS that restricts their malignant phenotype.

Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

“…Despite the apparent discrepancies concerning the role of UCP2 in carcinogenesis and cancer progression in different types of cells, e.g. UCP2 inhibition of apoptosis in hypoxia, our findings are in accordance with recent reports that UCP2 represses the malignant phenotypes of melanoma, glioma, and pancreatic cancer cells and that UCP2 deficiency mimics the effects of hypoxia in pulmonary hypertension [10, 11, 24, 25]. UCP2 was also shown to downregulate HIF-1, which, together with our finding that HIF-1 mediated hypoxia-triggered silencing of UCP2, suggests a regulatory circuit between UCP2 and HIF-1 determining the phenotypes of hypoxic malignant cells [10].…”

“…UCP2 plays a role in the regulation of cell survival by affecting ROS generation, redox status, and ATP production [9, 11]; therefore, we examined whether UCP2 is involved in the hypoxia-mediated desensitization of NSCLC cells to chemotherapy. Our results showed that UCP2 expression was downregulated in malignant tissues of patients with COPD and NSCLC compared with that in patients with NSCLC alone, suggesting a role of COPD-related hypoxia in regulating UCP2 expression (Figure 2A).…”

“…UCP2 regulates mitochondrial respiration and metabolism in many neoplastic cells [11]. To determine whether metabolic reprogramming is involved in the accelerated proliferation of UCP2-suppressed cells, we examined the glucose metabolism of cells exposed to different oxygen concentrations.…”

“…Disruption of UCP2 in mice triggers immune resistance to infection, suppresses inflammatory responses, and results in increased susceptibility to atherosclerosis, which are at least partially attributed to increased ROS production [10]. UCP2 plays a role in carcinogenesis in various tissues and regulates the responsiveness of carcinomas to chemotherapy [9, 11, 12]. However, the precise role of UCP2 in the chemotherapy sensitivity of tumors including NSCLC is currently under debate [9, 12].…”

Aberrant proliferation and differentiation of glycogen storage disease type Ib mesenchymal stem cells

“…HK2 is a predominant isoform in proliferating cells and its upregulation has been known to be a major contributor to the elevated glycolysis observed in many types of tumor cells [14]. In contrast, UCP2 expression level correlates negatively with proliferation of cancer cells [21], which also involves metabolic reprogramming, i.e., decreased glycolysis and increased oxidative phosphorylation in cancer cells overexpressing UCP2 [21]. This altered metabolism may inhibit adipogenic and osteogenic differentiation of G6PT À/À MSCs, since a metabolic switch from glycolysis to oxidative phosphorylation has been known to occur during adipogenic and osteogenic differentiation of MSCs derived from bone marrow and adipose tissues [22,23].…”