17. The Warburg Effect 

 

Otto Warburg established Warburg effect in 1923 as he detected that “An increase in glucose ingestion in cancer cells is related to restriction in oxygen consumption and lactic acid formation in aerobiosis” (Warburg O., 1923 as cited in Pascale R M et al., 2020) (Warburg O., 1924) (Pascale R M et al., 2020 as cited in Pascale R M et al., 2020).  Also, it has been observed that tumor development is associated with Warburg effect (Pascale R M et al., 2020).  

 

The Warburg Effect References

 

1.        Warburg, O. �ber den Stoffwechsel der Carcinomzelle. Naturwissenschaften 12, 1131–1137 (1924).

2.        Warburg, O. & Minami, S. Versuche an Überlebendem Carcinom-gewebe. Klin. Wochenschr. 2, 776–777 (1923).

3.        Pascale, R. M., Calvisi, D. F., Simile, M. M., Feo, C. F. & Feo, F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel). 12, 2819 (2020).

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17.1. The Regulatory Elimination of The Oxidative Metabolism in Cancer 

 

The oxidative activity of mitochondria, leading to ATP formation in normal cells, is ultimately consumed for ATP-related reactions in these cells (Pascale R M et al., 2020). However, the glycolytic glucose phosphorylation is raised in tumor cells and the formation of ATP through oxidative phosphorylation is decreased in these cells (Pascale R M et al., 2020). Furthermore, the net volume of oxygen ingestion is reduced in cancer cells due to  the minute number of minor dysfunctional mitochondria in these cells (Schreiber J R et al., 1970 as cited in Pascale R M et al., 2020) (Jiang F et al., 2000) (Claypool S M et al., 2008) (Kiebish M A et al., 2008) (Pascale R M et al., 2020). Additionally, a rise in lactic acid formation in neoplastic cells as a result of mitochondria failure to oxidise pyruvate, which is caused by the elimination of regulatory mechanisms in aerobiosis, is a significant event, when the analysis of the connection between respiration and glycolysis takes place in these cells (Pascale R M et al., 2020). Therefore, the role of HK2 (hexokinase 2) in the voltage-dependent anion channel Warburg effect becomes significant, as HK leaps to VDAC (Voltage-dependent anion channel) in the outer membrane of mitochondria, which results in relaxing interaction between HK and ATP produced in the inner membrane of mitochondria, increasing glucose metabolism and preventing apoptosis (Nakashima R A et al., 1986) (Arora K K and Pedersen P L., 1988 as cited in Pascale R M et al., 2020) (Pascale R M et al., 2020).  

 

The Regulatory Elimination of The Oxidative Metabolism in Cancer References

 

1.        Arora, K. K. & Pedersen, P. L. Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J. Biol. Chem. 263, 17422–8 (1988).

2.        Claypool, S. M., Oktay, Y., Boontheung, P., Loo, J. A. & Koehler, C. M. Cardiolipin defines the interactome of the major ADP/ATP carrier protein of the mitochondrial inner membrane. J. Cell Biol. 182, 937–950 (2008).

3.        Jiang, F. et al. Absence of Cardiolipin in the crd1 Null Mutant Results in Decreased Mitochondrial Membrane Potential and Reduced Mitochondrial Function. J. Biol. Chem. 275, 22387–22394 (2000).

4.        Kiebish, M. A., Han, X., Cheng, H., Chuang, J. H. & Seyfried, T. N. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer. J. Lipid Res. 49, 2545–2556 (2008).

5.        Nakashima, R. A., Mangan, P. S., Colombini, M. & Pedersen, P. L. Hexokinase receptor complex in hepatoma mitochondria: evidence from N,N’-dicyclohexlycarbodiimide-labeling studies for the involvement of the pore-forming protein VDAC. Biochemistry 25, 1015–1021 (1986).

6.        Pascale, R. M., Calvisi, D. F., Simile, M. M., Feo, C. F. & Feo, F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel). 12, 2819 (2020).

7.        Schreiber, J. R., Balcavage, W. X., Morris, H. P. & Pedersen, P. L. Enzymatic and spectral analysis of cytochrome oxidase in adult and fetal rat liver and Morris hepatoma 3924A. Cancer Res. 30, 2497–501 (1970).

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17.2. The Genes That Play Role in The Warburg Effect

 

PI3K/AKT pathway plays a role in glycolysis through the induction of a number of enzymes (Pascale R M et al., 2020). This procedure takes place as phosphoinositide-dependent kinase assists the attachment of AKT to the cell membrane (Pascale R M et al., 2020). 

 

PI3K/AKT is also responsible for the induction of glucose passage in addition to HK (hexokinase) and PFK (phosphofructokinase) (Xie Y et al., 2018) (Dimri M et al., 2020) (Pascale R M et al., 2020). Furthermore, as PI3K/AKT hinders the activation of GSK3β (Glycogen Synthase Kinase 3β) through its N-terminal serine phosphorylation, then the glycogen synthesis is reduced (Xie Y et al., 2018) (Pascale R M et al., 2020). This, in turn, causes mutation of p53 and other tumor suppressor genes as a result of the advancement of the cell cycle, which occurs as a consequence of the accretion of cyclin D1 (Xie Y et al., 2018) (Pascale R M et al., 2020). Furthermore, apoptosis is hindered through the AKT signalling pathway (Xie Y et al., 2018), which regulates the functionality of PFKFB3 (6-phosphofructo-2-kinase/fructose 2,6-biphosphatase 3) (Pascale R M et al., 2020). Also, elimination of hindering PFK2 (phosphofructokinase 2) by ATP takes place as a consequence of induction of PFK by AKT (Simon-Molas H et al., 2018 as cited in Pascale R M et al., 2020) (Villalobos P et al., 2016 as cited in Pascale R M et al., 2020) (Pascale R M et al., 2020).

 

Furthermore, the contribution of HIF1α in the glycolysis in anaerobiosis is explained by: (Mailloux R J and Appanna V D., 2007 as cited in Pascale R M et al., 2020) (Marín-Hernández  A et al., 2009 as cited in Pascale R M et al., 2020) (Cheng S C et al., 2014) (Pascale R M et al., 2020) and it is usually highly expressed in cancerous cells (Dang C V and Semenza G L., 1999 as cited in Pascale R M et al., 2020) (Gatenby R A and Gillies R J., 2004 as cited in Pascale R M et al., 2020) (Pascale R M et al., 2020).  The inducing role of HIF1α in glycolysis, activation of high expression of MYCand RAS and deficit in p53, are all known to be facilitated by the family of PFKFB proteins (Li F L et al., 2018) (Houddane A et al., 2017 as cited in Pascale R M et al., 2020) (Lee J H et al., 2017) (Gumińske M and Wazewska-Czyzewska M., 1975 as cited in Pascale R M et al., 2020) (Pascale R M et al., 2020).     

 

The Genes That Play Role in The Warburg Effect References

 

1.        Cheng, S.-C. et al. mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity. Science (80-. ). 345, (2014).

2.        Dang, C. V & Semenza, G. L. Oncogenic alterations of metabolism. Trends Biochem. Sci. 24, 68–72 (1999).

3.        Dimri, M. et al. NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3‐Kinase/Akt Serine/Threonine Kinase and Mitogen‐Activated Protein Kinase/Extracellular Signal‐Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma. Hepatology 71, 549–568 (2020).

4.        Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004).

5.        Gumińska, M. & Ważewska-Czyżewska, M. Enzymatic pattern of glucose metabolic pathways in pyruvate kinase-deficient erythrocytes. Clin. Chim. Acta 64, 165–172 (1975).

6.        Houddane, A. et al. Role of Akt/PKB and PFKFB isoenzymes in the control of glycolysis, cell proliferation and protein synthesis in mitogen-stimulated thymocytes. Cell. Signal. 34, 23–37 (2017).

7.        Lee, J.-H. et al. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat. Commun. 8, 949 (2017).

8.        Li, F.-L. et al. Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. Nat. Commun. 9, 508 (2018).

9.        Mailloux, R. J. & Appanna, V. D. Aluminum toxicity triggers the nuclear translocation of HIF-1α and promotes anaerobiosis in hepatocytes. Toxicol. Vitr. 21, 16–24 (2007).

10.     Marin-Hernandez, A., Gallardo-Perez, J., Ralph, S., Rodriguez-Enriquez, S. & Moreno-Sanchez, R. HIF-1α Modulates Energy Metabolism in Cancer Cells by Inducing Over-Expression of Specific Glycolytic Isoforms. Mini-Reviews Med. Chem. 9, 1084–1101 (2009).

11.     Pascale, R. M., Calvisi, D. F., Simile, M. M., Feo, C. F. & Feo, F. The Warburg Effect 97 Years after Its Discovery. Cancers (Basel). 12, 2819 (2020).

12.     Simon-Molas, H. et al. PI3K–Akt signaling controls PFKFB3 expression during human T-lymphocyte activation. Mol. Cell. Biochem. 448, 187–197 (2018).

13.     Villalobos, P., Soto, F., Baez, M. & Babul, J. Regulatory network of the allosteric ATP inhibition of E. coli phosphofructokinase-2 studied by hybrid dimers. Biochimie 128–129, 209–216 (2016).

14.     Xie, Y. et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol. Med. Rep. (2018). doi:10.3892/mmr.2018.9713