Abstract
Overexpression of the Ski oncogene induces oncogenic transformation of chicken embryo fibroblasts (CEFs). However, unlike most other oncogene-transformed cells, Ski-transformed CEFs (Ski-CEFs) do not display the classical Warburg effect. On the contrary, Ski transformation reduced lactate production and glucose utilization in CEFs. Compared with CEFs, Ski-CEFs exhibited enhanced TCA cycle activity, fatty acid catabolism through β-oxidation, glutamate oxidation, oxygen consumption, as well as increased numbers and mass of mitochondria. Interestingly, expression of PPARγ, a key transcription factor that regulates adipogenesis and lipid metabolism, was dramatically elevated at both the mRNA and protein levels in Ski-CEFs. Accordingly, PPARγ target genes that are involved in lipid uptake, transport, and oxidation were also markedly up-regulated by Ski. Knocking down PPARγ in Ski-CEFs by RNA interference reversed the elevated expression of these PPARγ target genes, as well as the shift to oxidative metabolism and the increased mitochondrial biogenesis. Moreover, we found that Ski co-immunoprecipitates with PPARγ and co-activates PPARγ-driven transcription.
Highlights
Oncogenic transformation is usually accompanied by increased aerobic glycolysis, lipid metabolism, and glutamine catabolism
These results suggest that the observed enhancement of tricarboxylic acid (TCA) cycle flux in Ski-chicken embryo fibroblasts (CEFs) is in part driven by the increased acetyl-CoA produced by fatty acid -oxidation
In this study we have delineated a molecular mechanism by which Ski shifts the energy metabolism of CEFs from glycolysis to enhanced rates of fatty acid oxidation and oxidative phosphorylation
Summary
Oncogenic transformation is usually accompanied by increased aerobic glycolysis, lipid metabolism, and glutamine catabolism. Transgenic mice overexpressing c-Ski exhibit a remarkable increase of skeletal muscle mass but a decrease of adipose tissue [17] In these mice, selective hypertrophy of type IIb fast skeletal muscle fibers is accompanied by increased lipid oxidation despite decreased expression of the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥), a key regulator of lipogenesis [17]. Selective hypertrophy of type IIb fast skeletal muscle fibers is accompanied by increased lipid oxidation despite decreased expression of the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥), a key regulator of lipogenesis [17] These findings suggest that Ski plays a role in regulating lipid metabolism, perhaps mediated by an effect on the expression or transcriptional activity of PPAR␥. We demonstrate that Ski has a profound effect on cellular energetics by decreasing the reliance on glycolysis and stimulating biogenesis of mitochondria and lipid oxidation
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