Cancer cells continue to trick mammalians and seek immortality. Although, cancer cells tend to use glucose during aerobic glycolysis to provide the building blocks, the case is different under metabolic stress. The glucose flux is being directed to go through the pentose phosphate pathway (PPP) for the generation of NADPH instead of going through aerobic glycolysis. During economic depression, cancer cells reprogram their metabolic homeostasis in order to survive mainly on mitochondrial oxidative phosphorylation. Thus, NADPH is needed for cancer to survive the oxidative stress.
The transcriptional repressor of epithelial–mesenchymal transition (EMT) called Snail (SNAI1) has been involved in directing the glucose flux. Snail controls the activity of phosphofructokinase, platelet (PFKP), an isomer of phosphofructokinase (PFK-1). One of the important steps in the mammalian glycolytic pathway is catalyzed by phosphofructokinase-1 (PFK-1) which converts fructose-6-phosphate (F6P) into fructose-1, 6-bisphosphate (F1, 6BP). PFK-1 is usually inhibited when the cell has enough energy, but here Snail-PFKP axis is the boss.
The knockdown of SNAI1, weakened the cells mostly in the early glucose starvation process. As well, Slug (SNAI2) is another EMT inducer which gave the same result as SNAI1 in overcoming the glucose starvation or paclitaxel treatment. Furthermore, the author introduced a human breast adenocarcinoma cells (MDA-MB-231) without extracellular matrix into tail vein. Then, the Snail was knocked down eliminating the metastatic potential. While, the overexpression of Snail increased the cancer metastatic ability. Cancer cells detachment is also important for their survival and requires the Snail richness.
The reactive oxygen species (ROS) and NADPH ratios were measured to for a better metabolic linking between cell death and Snail richness. An increased ROS levels and decreased levels of NADPH in breast cancer cells due to the author shutting down of Snail. However, Snail is steal in control of NADPH via PPP. NADPH imbalance will cause a shock to the cancer cells in an oxidative stressful state.
On a journey to further understand the function of Snail on glucose metabolism, the author focused on Snail abundance through metabolic profiling using 1H-NMR spectroscopy. Amino acids such as glycine were increased. Endogenous intermediate metabolites of aerobic glycolysis and lactate were also increased. The levels of 13C-glucose to 13C-lactate were increased and traced down after the knockdown of Snail in MDA-MB-231 cells. Snail again is identified as able to reprogram the pathway and repress the glycolytic flux in breast cancer cells. Additionally, PFKP was tested to see if it links to cancer survival and metabolic reprogramming. Upon suppression, PFKP was found to be opposed to Snail, and it increased cancer cell survival in vivo. When PFKP repressed, it increased the amount of ribulose-5-phosphate supporting that it regulates glucose flux into PPP in cancer cells. Also, PFKP loss repressed lactate production and amino acids and increased the levels of NADPH. The lactate and NADPH production after Snail taking out was fixed by inducible knockdown of PFKP. The overexpression of PFKP saved the Snail-mediated metabolic reprogramming. Therefore, PFKP also has an important role of regulation in breast cancer cells.
The aerobic glycolysis and the pentose phosphate pathway and many others are important in driving the energy in living mammalian cells. They are worth studying in order to understand the Snail-PFKP axis and how they help cancer cells grow and divide. The pathways are the focus of every biochemist. The paper proved the Snail-PFKP axis to be a significant point in controlling the aerobic glycolysis. A clear understanding of the Snail-PFKP axis metabolic reprogramming, it will demolish the cancer stemness and its therapeutic resistance. As the cancer continues to survive, research on ways to end it will continue. More testing is needed to understand stem cells and the processes of differentiation and survival under stress. These cells are able to multiple and grow quickly unless manipulated. NADPH is released in great amounts when the switch is on the PPP. It might be the only way for cancer cells to fight their oxidative stress. But as always known, cancer cells continue to find a leak in the cellular processes of mammalians.
- Kim, N. H. et al. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress. Nature Communications 8, 14374 (2017).
- “Additional MDA-MB-231 breast cancer cell matrix metalloproteinases promote invasiveness.” Journal of cellular physiology.S. National Library of Medicine, n.d. Web. 20 Feb. 2017.
- Mayo, Dave. “The Pentose Phosphate Pathway: The missing link between hormonal imbalances and carbohydrate metabolism?” The Pentose Phosphate Pathway: The missing link between hormonal imbalances and carbohydrate metabolism? N.p., 01 Jan. 1970. Web. 20 Feb. 2017.
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