Abstract
BackgroundIn the last decades, the concept of metabolic rewiring as a cancer hallmark has been expanded beyond the “Warburg effect” and the importance of other metabolic routes, including lipid metabolism, has emerged. In cancer, lipids are not only a source of energy but are also required for the formation of membranes building blocks, signaling and post-translational modification of proteins. Since lipid metabolism contributes to the malignancy of cancer cells, it is an attractive target for therapeutic strategies.MethodsOver-expression of the adipose triglyceride lipase (ATGL) was used to boost lipid catabolism in cervical cancer cells. The cervical cancer cell line HeLa was employed as the primary experimental model for all subsequent studies. The lipolytic activity of ATGL was mimicked by caproate, a short-chain fatty acid that is efficiently oxidized in mitochondria.ResultsHere, we provide evidence of the association between boosted lipid catabolism and the increased proliferation and migration capability of cervical cancer cells. These pro-tumoral effects were ascribed to the reactive oxygen species (ROS)-mediated induction of hypoxia-inducible factor-1α (HIF1α) triggered by the increased mitochondrial fatty acids (FAs) oxidation. HIF1α activation increases glycolytic flux and lactate production, promoting cell proliferation. At the same time, HIF1α increases protein and mRNA levels of its known target BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), which in turn activates mitophagy as a pro-survival process, as demonstrated by the induction of apoptosis upon inhibition of mitophagy. These effects were mimicked by the short-chain fatty acid caproate, confirming that forcing lipid catabolism results in HIF1α induction.ConclusionsBoosting lipid catabolism by ATGL over-expression has a pro-tumor role in cervical cancer cells, dependent on ROS production and HIF1α induction. Together with the bioinformatics evidence of the correlation of ATGL activity with the aggressiveness of cervical cancer cells, our data suggest that ATGL could be a promising prognostic marker for cervical cancer and highlight the need of further investigations on the role of this lipase in cancer cells. This evidence could be exploited to develop new personalized therapy, based on the functionality of the antioxidant equipment of cancer cells, considering that ROS content could affect ATGL role.
Highlights
In the last decades, the concept of metabolic rewiring as a cancer hallmark has been expanded beyond the “Warburg effect” and the importance of other metabolic routes, including lipid metabolism, has emerged
Adipose triglyceride lipase (ATGL) over-expression is associated with an increased proliferation rate in cervical cancer cell lines To investigate the role of intracellular lipolysis and lipid metabolism in cervical cancer, we over-expressed the lipase ATGL and we assessed whether the proliferative capacity of cervical cancer cells was affected
In support of the hypothesis that lipolysis promotes the aggressive phenotype of HeLa cells, over-expression of ATGL was associated with increased nuclear β-catenin (Fig. 2d), a marker of cancer cell invasion [24, 25] and the up-regulation of its known target and angiogenesis factor Vascular endothelial growth factor (VEGF) [26] (Fig. 2e)
Summary
The concept of metabolic rewiring as a cancer hallmark has been expanded beyond the “Warburg effect” and the importance of other metabolic routes, including lipid metabolism, has emerged. Metabolic plasticity enables cancer cells to switch between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis in response to intracellular signaling pathways and environmental cues. It is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities. The switch from oxidative to glycolytic metabolism in the presence of oxygen -known as the “Warburg effect”- is a cancer cell strategy to survive by exploiting a rapid glucose-derived source for energy and for anabolism [1]. HIF1α increased the proliferation rate and “Warburg effect”, as well as it triggered BCL2 and adenovirus E1B 19-kDainteracting protein 3 (BNIP3)-mediated mitophagy as a survival mechanism
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