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. 2013:2013:109285.
doi: 10.1155/2013/109285. Epub 2013 Feb 3.

Therapeutic implications of targeting energy metabolism in breast cancer

Meena K Sakharkar  1 , Babita Shashni, Karun Sharma, Sarinder K Dhillon, Prabhakar R Ranjekar, Kishore R Sakharkar
Affiliations

Therapeutic implications of targeting energy metabolism in breast cancer

Meena K Sakharkar et al. PPAR Res. 2013.

Abstract

PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.

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Figures

Figure 1
Figure 1
PPAR gamma activation mechanism. PPRE and PACM motifs are shown.
Figure 2
Figure 2
PPAR gamma gene targets and their pathways.
Figure 3
Figure 3
Tumor cells have altered glucose metabolism. Many glycolytic enzymes are ubiquitously expressed in cancers. One such glycolytic enzyme is pyruvate kinase type M2 whose levels are found to be elevated in human cancer biopsies, compared to adjacent normal tissues. PKM2 is a key regulator of the metabolic budget system in tumor cells which promotes the Warburg effect and tumor growth. This tumor specific PKM2 can be switched between dimeric and tetrameric forms in cancer cells. Dimeric PKM2 has a higher K m value for the substrate PEP than the tetrameric form of PKM2 and is inactive at physiological concentrations of PEP. PKM2 is allosterically activated by the glycolytic metabolite fructose-1,6-biphosphate (FBP) and serine. This leads to accumulation of energy rich phospho metabolites upstream of glycolytic pathway which are then channelled to macromolecule biosynthesis via pentose phosphate pathway (PPP). These pathways include pyrimidine, glycerol, and serine/glycine biosynthesis (red arrows) instead of leading to oxidative metabolism for energy production thereby promoting cancer cell proliferation and tumor growth.
Figure 4
Figure 4
PPAR gamma disease gene network. Rectangles represent genes and circles represent diseases. Only genes involved in more than one disease are shown.
See this image and copyright information in PMC

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