Editors' ChoiceCancer

Rewiring the Metabolism of Cancer Cells

Sci. Signal.  14 Oct 2014:
Vol. 7, Issue 347, pp. ec282
DOI: 10.1126/scisignal.aaa0412

Cancer cells have altered glucose, lipid, and glutamine metabolism that enable the proliferation of the cells. The transcription factor peroxisome proliferation–activated receptor γ (PPARγ) controls the expression of genes involved in lipid and glucose metabolism and thiazolidinediones (TZDs) were developed as agonists of this receptor to treat type 2 diabetes, but have been repurposed as oncogenic therapies. Srivastava et al. determined how PPARγ agonists blocked proliferation in cultured cancer cells lines and tumors xenografted into mice. Chromatin immunoprecipitation analysis of the genes that bound PPARγ in cancer cell lines exposed to TZDs and analysis of the transcriptional response from 12 to 48 hours indicated that direct target genes of PPARγ that were stimulated as part of the earliest response included genes encoding proteins involved in lipid metabolism, in particular PDK4, which encodes pyruvate dehydrogenase kinase 4. At later times, transcripts encoding proteins involved in cell cycle progression were reduced and transcripts encoding proteins involved in the oxidative stress response were increased. Thus, PPARγ appeared to alter lipid metabolism leading to an increase in reactive oxygen species (ROS) that inhibited the cell cycle. Consistent with this hypothesis, only cancer cells positive for PPARγ, not those with low abundance of endogenous PPARγ or in which PPARγ was knocked down, exhibited a decrease in the phosphorylation of the cell cycle protein retinoblastoma (Rb) in response to TZD exposure. In cancer cell lines with PPARγ, TZD exposure also stimulated an increase in ROS and blocking this increase with antioxidants prevented the decrease in Rb phosphorylation. The inhibition of xenografted tumor growth by TZD treatment was also blocked by cotreatment with antioxidant or by knocking down PPARγ in the cells. PDK4 phosphorylates and inhibits pyruvate dehydrogenase, triggering a switch from glucose oxidation to fatty acid oxidation; expression of this gene is often reduced in solid tumors. Inhibition or knockdown of PKD4 blocked the TZD-mediated reduction in Rb phosphorylation and increase in ROS. Inhibition of PDK4 also prevented TZD treatment from suppressing xenografted tumor growth. Analysis of the metabolic changes in TZD-exposed cells revealed an increase in glucose consumption, increased lactate secretion, reduced conversion of glutamine to glutamate, and reduced glutathione (a molecule synthesized from glutamate and involved in ROS detoxification), consistent with a switch in metabolism that impaired the cell’s ability to cope with oxidative stress. Glutaminase inhibition or glutamine deprivation reduced Rb phosphorylation and increased ROS in cultured cells and inhibited xenografted tumor growth. Thus, PPARγ agonists alter cellular metabolism thereby impairing the oxidative stress response and inducing growth arrest.

N. Srivastava, R. K. Kollipara, D. K. Singh, J. Sudderth, Z. Hu, H. Nguyen, S. Wang, C. G. Humphries, R. Cartens, K. E. Huffman, R. J. DeBerardinis, R. Kittler, Inhibition of cancer cell proliferation by PPARγ is mediated by a metabolic switch that increases reactive oxygen species levels. Cell Metab. 20, 650–661 (2014). [PubMed]