By Hung-Hsi (Chelsea) Chen
People say that cancer is triggered by mutations in cells, which eventually lead to uncontrolled cell proliferation. However, DNA mutations occur all the time, even up to a trillion mutations a day. To come up with treatments, it is imperative to understand how cancer cells differ from normal cells, in terms of the way they metabolise and utilise these nutrients, otherwise known as alterations in metabolism, an emerging hallmark of cancer.
Alterations in metabolism show cancer cells reprogram their metabolism to cope with the fast pace of growth, Normal cells in the body receive blood supply rich in oxygen and nutrients. Therefore, they can afford to undergo aerobic respiration to yield energy in the form of ATP. In contrast, cancer cells proliferate much faster than normal cells, which results in them outgrowing their local blood supply, therefore causing the center of the tumor to become hypoxic. For this reason, Hypoxia Inducible Factor (HIF-1a) degradation is inhibited, to support glucose metabolism via glycolysis in the absence of oxygen, which links to aerobic glycolysis.
Aerobic glycolysis was first observed in the 1920s by Otto Warburg, and it is commonly known as the Warburg effect. He saw a dramatic increase in glucose uptake and lactate excretion in tumor cells compared to the surrounding tissue. A surprising observation was that instead of the efficient ATP synthesis pathway via aerobic respiration, cancer cells utilise glycolysis for glucose metabolism even in normoxic conditions. this is due to the resulting macromolecule precursors. The body gets its carbon, nitrogen, free energy and reducing equivalent supplies from catabolising glucose and glutamine (Cho et al., 2018). For example, acetyl-CoA is used for fatty acids synthesis and glycolytic intermediates for amino acids synthesis.
Furthermore, metabolites produced during glycolysis are carried to the pentose phosphate pathway to produce ribose-5-phosphate, which is used to create nucleotides and NADPH (Cho et al., 2018). NADPH is used in cancer cells for fatty acid synthesis and reduce glutathione for building resistance against chemotherapeutic agents (Yu et al., 2017, Traverso et al., 2013). Understanding the basis of chemotherapeutic resistance helps us understand how drug resistance observed in cancer cells can be targeted for future therapies.
A key player mentioned earlier in inducing the Warburg effect in cancer cells is Hypoxia Inducible Factors, and it is made up of two subunits: HIF- α and HIF- β. HIF-α is stabilized by coactivator proteins during hypoxic conditions, allowing them to be translocated to the nucleus to bind to HIF- β, creating a heterodimeric transcription factor, HIF-1.
As aforementioned, hypoxic conditions trigger the inhibition of HIF-1 degradation, and HIF-1 activation is associated with glucose transporter and glycolytic enzyme upregulation (Mei et al., 2009). HIF-1 activation induces pyruvate dehydrogenase kinase 1 transcription, which inhibits pyruvate dehydrogenase to convert pyruvate into acetyl-CoA, hence suppressing Krebs cycle progression. Therefore, glucose metabolism via aerobic glycolysis is favoured over oxidative phosphorylation.
Pyruvate dehydrogenase kinase 1 has another role in cancer metabolism by acting on the PI3K/Akt/mTOR pathway, a pathway that regulates cancer metabolism, proliferation and glycolysis. In this pathway, Akt is a serine/threonine kinase, also known as Warburg kinase, acts as a glycolytic switch for cancer cells in non-hypoxic environments. Akt is activated through phosphorylation by PDK1, which serves to change cellular metabolism and shifts glucose metabolism towards glycolysis (Yu et al., 2017).
Another way cancer cells compensate for the inefficient ATP production in cancer cells is by prohibiting pyruvate from entering the mitochondria. Enzyme lactate dehydrogenase degrades pyruvate into lactate, which enters the Cori cycle, where lactate gets circulated to the liver to be converted back to glucose and released into the bloodstream. The glucose gets back to the proliferating cells to undergo aerobic glycolysis once more, leading to a cycling loop for the cell to create ATP. Unfortunately, a lot of energy in the form of ATP is required for the reversion of lactate into glucose, and creates a side effect experienced by the host called cancer cachexia.
As one of the emerging hallmarks of cancer, altered metabolism, specifically relating to the Warburg effect, can be used as a target for cancer therapy. One aspect of the Warburg effect that could be targeted for therapy is the metabolic-related enzymes or proteins, such as HIF-1. These chemotherapeutic agents could either be inhibitors of transcription and translation of HIF-1 alpha, promoters of HIF-a degradation or inhibitors of DNA binding and transactivation (Mei, 2009).
Unfortunately, the ability for cancer cells to transition between one metabolic pathway to the other may result in chemoresistance or failure in therapy in cancer patients. Therefore, understanding the basis of cancer cell metabolism and the cause of therapy resistance need to be considered as a future therapeutic target.
Cho, E.S., Cha, Y.H., Kim, H.S., Kim, N.H. & Yook, J.I. 2018, “The Pentose Phosphate Pathway as a Potential Target for Cancer Therapy”, Biomolecules & therapeutics, vol. 26, no. 1, pp. 29-38.
Mei, Y.K., Taly R. Spivak-Kroizman & Powis, G. 2009, “Inhibiting the Hypoxia Response for Cancer Therapy: The New Kid on the Block”, Clinical Cancer Research, vol. 15, no. 19, pp. 5945-5946.
Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A.L., Pronzato, M.A., Marinari, U.M. & Domenicotti, C. 2013, “Role of Glutathione in Cancer Progression and Chemoresistance”, Oxidative medicine and cellular longevity, vol. 2013, pp. 1-10.
Yu, L., Chen, X., Sun, X., Wang, L. & Chen, S. 2017a, “The Glycolytic Switch in Tumors: How Many Players Are Involved?”, Journal of Cancer, vol. 8, no. 17, pp. 3430-3440.