Cancer cell metabolism

Cancer cells mainly utilize their energy source from glucose, a simple sugar. But unlike the normal cells, in spite of the presence of ample oxygen, cancer cells prefer to metabolize glucose through aerobic gycolysis, which is often considered as a less efficient pathway for producing ATP [1, 3, 5, 6, 7]. This marked metabolic alteration in cancer cells is discovered during the 1920s by Warburg. Since then, many research investigations have supported this finding. Currently, the Warburg effect or aerobic glycolysis, the conversion of glucose to lactic acid in the presence of oxygen, is generally accepted as a metabolic landmark of malignant cancer cells [1, 3, 5, 6, 7]. Increased aerobic glycolysis as distinctively observed in cancers led Warburg to hypothesize that cancer results from impaired mitochondrial metabolism [4].

Similar to obligate and facultative anaerobic bacteria that can still obtain energy and maintain life without oxygen, studies suggest that aerobic glycolysis, a pathway that does not require oxygen, might be essential for cancer progression [5, 6, 7, 8]. In a more recent research, the Warburg effect is considered not only an outcome of transformation of the normal and functional cells to cancer cells, but it is recognized as a necessary event before the initiation of any cellular transformation [5]. The results of one study revealed that cancer cells need to shift their metabolism toward aerobic glycolysis in order to prevent cell death [9]. The fluorodeoxyglucose positron emission tomography or FdG PET, an imaging technique, revealed that the most primary and metastatic cancers show significant increase in glucose uptake. Noteworthy to mention, the increased glucose uptake obtained by FdG PET is mainly dependent on the rate of glycolysis [10]. Studies show that increased glucose uptake consistently correlated to poor prognosis and increased aggressiveness of the tumor [11, 12, 13, 14]. Research groups have also demonstrated that hypoxic tumors that necessitate increased glycolysis are more frequently invasive and aggressive than those tumors with normal levels of oxygen [16, 17, 18].

It is believed that the altered metabolism of cancer cells creates a unique tumor environment. As the tumor increase its size, it surpasses the limits of its local blood supply, which consequently results in hypoxia and stabilization of the hypoxia-inducible factor-1α or HIF-1α [6, 15]. It is thought that HIF-1α mediates multiple solutions to hypoxic stress [7]. Overexpression of HIF-1α found in different human cancers maintains the survival of cancer cells by the following ways:

  • Stimulates angiogenesis, or the formation of new blood vessels by upregulating vascular endothelial growth factor or VEGF. The formation of additional blood vessels is necessary for tumor survival, increasing its vascularity [3, 6].
  • Increases all the enzymes in glycolytic pathway and glucose transporters 1 and 3 [18]. Research reveals that the products of glycolysis, such as lactate and pyruvate cause the accumulation of HIF-1α in the presence of oxygen, suggesting a possible positive feedback loop [15].
  • Induces insulin-like growth factor-2 or IGF-2 and transforming growth factor-α or TGF-α, which not only encourage cancer cell proliferation and survival, but also increase the expression of HIF-1α itself [15, 18].
  • Stimulate pyruvate dehydrogenase kinase, which consequently, inactivates the enzyme pyruvate dehydrogenase or PDH found in the mitochondria. This enzyme is mainly responsible in converting pyruvate to acetyl – CoA. Thus, the inactivation of this enzyme results in the inhibition of the conversion of pyruvate to acetyl – CoA. Bear in mind that there is a need for the formation of acetyl – CoA to proceed with citric acid cycle and oxidative phosphorylation. Since pyruvate is not further metabolized, glycolytic shift occurs and aerobic glycolysis persists.
  • Increases the levels of phosphorylation of Akt. The activation of Akt kinase pathway is considered as the main force of the Warburg effect [6]. The activation of the oncogene Akt stimulates the switch toward aerobic glycolysis. Additionally, Akt activation maintains cell growth and resistance to apoptosis or programmed cell death.

Acidification in cancer cells

The aforementioned events in cancer and the distinctive upregulation of glycolysis in tumor cells appear as effective adaptations to hypoxia [5, 6, 7]. Persistent activation of glycolysis results in increased production of lactic acid, which causes acute and chronic acidification of the tumor’s local environment [5, 6, 7]. It has been reported that the production of lactic acid in cancer cells is 40 times more than the amount that the normal cells do, resulting in acidification of their environment [18].

In cancer cells, pyruvate is formed, as the normal cells do. However, due to poor vascularization of tumors and their switch toward the glycolytic pathway, pyruvate is reduced to lactate through the Cori’s cycle, generating 2 molecules of ATP, which is much less compared to the number of ATPs produced through oxidative phosphorylation. To keep up with the demands of cancerous cells for ATP, the rate of glycolytic pathway is increased, which consequently, results in increased production of lactic acid. Studies that have shown that the extracellular pH of both human and animal cells with cancer is consistently acidic, reaching the pH of 6.0 [19, 20, 21]. The optimum pH for normal human cells is slightly alkaline, ranging from 7.35 to 7.45, with an ideal pH measurement of 7.4.

Bacterial Metabolism

Much like the human cancer cells, bacteria make use of certain pathways of metabolism to obtain the energy needed to support their growth and reproduction and to create the environment where they can thrive and survive. Similar to cancer cells, all bacteria must be able to utilize their energy sources available in their environment to generate ATP, which is a requirement for all biosynthetic processes to maintain their growth and reproduction. Bacteria synthesize and produce enzymes that allow them to oxidize the energy sources or fuels in their environment. In the next section, the similarities of cancer cell and bacterial metabolism are thoroughly discussed.

The bacteria that infect humans seem to obtain their energy through the use of organic compounds, deriving energy from oxidation reactions. Although these compounds vary between carbohydrate, amino acids, fatty acids, purines and pyrimidines, most bacteria that are linked to human infections favor glucose as a principal fuel, which is much like the cancer cells [6, 7]. Many bacteria use glucose as many possess the enzymes needed for their degradation and oxidation [22, 23, 24].

Bacteria are known to utilize a wide range of organic compounds as their source of carbon, which includes carbohydrates, proteins and lipids. It is important to emphasize that bacteria do not possess distinct metabolic pathways for each substrate. They usually convert the substrate into a form that is utilized by the central pathways.

Most bacteria generate ATP through glucose degradation [22, 23]. The initial steps of glucose breakdown occur according to the Embden-Mayerhof glycolitic pathway, resulting in pyruvate as its intermediate product. This process does not require oxygen; thus, anaerobic bacteria can still obtain energy by splitting the glucose molecule and removing the electrons from the molecule.

Aerobic bacteria oxidize pyruvate to CO2 and H2O. The reduction of oxygen is coupled to the electron transport coupled phosphorylation, whose enzymes are located in the bacterial inner or cytoplasmic membrane [25]. Bacteria that tolerate or require anoxic conditions utilize organic or inorganic electron acceptors, instead of oxygen, to generate energy. For anaerobic that live in the absence of inorganic electron acceptors, such as in the intestinal tract, they generate energy through fermentation. Pyruvic acid is converted into an end product. The specific end product would mainly depend on the specific organism involved. Some bacteria convert pyruvic acid into lactic acid, such as in certain Streptococci species, whereas, other bacteria convert it to propionic acid. Anaerobically, Helicobacter pylori metabolized pyruvate to lactate, ethanol and acetate [26]. Other end products of fermentation include acetone, acetic acid, butyric acid, butanol, isopropanol, ethyl alcohol and succinic acid. The pk values of some these acids are 3.86 for lactate, 4.75 for acetate, and 4.82 for butyric acid, which can decrease the environment’s pH, promoting acidification.

For bacteria to grow and survive, in addition to a suitable and adequate energy source, they need the appropriate environmental conditions, such as the right nutrients, correct temperature and gaseous requirements. Additionally, bacteria need an optimum pH inside their cells, just like all the other living organisms to maintain survival. Their ability to survive in environments with extreme pH mainly depends on their ability to adjust or adapt to these changes. Helicobacter pylori, which has a metabolic range between an environmental pH of 3.5 and 8.0, has been known to live in acidic environments in the stomach [27]. It was found that this bacterium is able to withstand the usually destructive acidic environment by producing large amounts of urease, the enzyme that catalyzes the hydrolysis of urea into water and carbon dioxide, which in turn, decreases the acidity in their environment and increases tolerance to acidic environments to survive [24, 27].

The growth and the rate of reproduction of bacteria are greatly affected by the pH of their environment. Generally, most bacteria that inhabit and infect humans grow best at pHs on the acid side of the neutrality. However, most bacteria are able to tolerate a range of pH values that extend on either side of their pH optimum as a bell-shaped curve. This is mainly because within their limits, bacteria can react and adjust to these changes through altering the patterns of biochemical processes.

Unlike mammalian and plant cells, most bacteria are constantly exposed to changes in their physical and chemical environment. Bacteria have developed various mechanisms to control their metabolism. If the end product of a certain pathway is not needed or if it can be readily availed in their environment, they shut down the involved biosynthetic pathways. Bacterial cells have this inherent ability to determine whether the conditions that surround them can be harmful or beneficial for their survival and most importantly, to make the necessary adaptations. A crisis command center was discovered by Mari van Heel and colleagues [28]. The author revealed that any condition that threatens the survival of the bacteria relays a warning signal from its surface into the inside of the cell, triggering a cascade of signals that result in the production of proteins that are able to adapt and survive in its environment. Similar to bacteria, cancer cells are also adaptive to their environment; thus total eradication continues to be a challenge for clinicians.  Gatenby and Gillies propose that the remarkable upregulation of glycoloysis in cancer cells is their way of adapting to environment growth constraints during carcinogenesis [7]. Aerobic glycolosis is often regarded as the hallmark of invasive cancers [5, 6, 7], thus it may be considered a successful adaptation to hypoxia or anoxia [7].

An Exclusive Article for Members
From THE BRIDGE Newsletter of OIRF
Published June 2010

© Copyright 2010, Dr. Karim Dhanani, ON Canada

About the author

LITERATURE:

  1. Carew J, Huang, P: Mitochondrial defects in cancer. Molecular Cancer 2002, 1(9)
  2. Warburg O: On the origin of cancer cells. Science 1956, 123:309-314.
  3. Garber K: Energy boost: the Warburg effect returns in a New Theory of Cancer. Journal of the National Cancer Institute 2004, 96(24):1805-1806.
  4. Hsu, P, Sabatini, D: Cancer cell metabolism: Warburg and beyond. Cell 2008, 134:703-707.
  5. Gatenby R, Gillies, R: Why do cancers have high aerobic glycolysis? Nature 2004, 4:891-899.
  6. Wang X. The expanding role of mitochondria in apoptosis. Genes & Development 2001, 15:2922-2933
  7. Singh KK, Russell, J, Sigala B, Zhang, T, Williams J, Keshav KF: Mitochondrial DNA determines the cellular response to cancer therapeutic agents. Oncogene 1999, 18: 6641-6646.
  8. Hawkins RA, & Phelps: PET in clinical oncology. Cancer Metastasis Rev. 7, 119–142 (1988).
  9. Weber, W. A., Avril, N. & Schwaiger, M. Relevance of positron emission tomography (PET) in oncology. Onkol. 175, 356–373 (1999).
  10. Gambhir, SS: Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002).
  11. Kunkel M. et al: Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer 97, 1015–1024 (2003).
  12. Mochiki, E. Evaluation of 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography for gastric cancer. World J. Surg. 28, 247–253 (2004).
  13. Ke Q, Costa M: Hypoxia-inducible factor-1 (HIF-1). Molecular Pharmacology Fast Forward 2006, 70:1469-1480.
  14. Schistosomes, Liver Flukes and Helicobacter pylon. Monographs on the Evaluation of Carcinogenic Risks to Humans 1994, 61.
  15. Parsonnet J. Friedman GD, Vandersteen DP, Chang Y, Vogelman, JH, Orentreich N, Sibley RK: Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991, 325(16):1127-1131.
  16. John A: Oxygen and cancer cells. Medical Hypotheses 2001, 57(4):429-431.
  17. Morita T, Nagaki T, Fukuda I, Okumura, K: Clastogenicity of low pH to various cultured mammalian cells. Mutation Research 1992, 268:297-305
  18. Ruch RJ, Launig, JE, Kerckert, GA, LeBoeuf RA: Modification of gap junctional intercellular communication by changes in extracellular pH in syrian hamster embryo cells. Carcinogenesis 1990, 11:909-913.
  19. Martinez-Zaguilan, R et al. Acidic pH enhances the invasive behavior of human melanoma cells. Clinical & Experimental Metastasis 1996, 14:176-186.
  20. Jaradat, Z, Bhunia, A: Glucose and nutrient concentrations affect the expression of a 104-kilodalton Listeria adhesion protein in Listeria monocytogenes. Applied and Environmental Microbiology 2002, 68(10):4876-4883.
  21. Sato, F et al: Ultrastructural observation of Helicobacter pylori in glucose-supplemented culture media. Journal of Medical Microbiology 2003, 52:675-679.
  22. Hardy, S: Human Microbiology, 2002. New York: Taylor & Francis, Inc.
  23. Baron, S: Medical Microbiology 4th, 1996 Texas: The University of Texas Medical Branch.
  24. Chalk P, Roberts A, Blows M: Metabolism of pyruvate and glucose by intact cells of Helicobacter pylori studied by 13C NMR spectroscopy. Microbiology 140:2085-2092.
  25. Rektorschek M, Weeks D, Sachs G, Melchers K: Influence of pH on metabolism and urease activity of Helicobacter pylori, Gastroenterology 1998, 115:628-641.
  26. Imperial College London (2008, October 3). Don’t Stress! Bacterial Cell’s ‘Crisis Command Center’ Revealed. ScienceDaily. Retrieved October 26, 2009, from http://www.sciencedaily.com­ /releases/2008/10/081002172007.htm.
  27. Travagione S, Fabbri A, Fiorentini C: The Rho-activation CNF1 toxin from pathogenic E. coli: A risk factor for human cancer development. Infectious Agents & Cancer 2008, 3(4)
  28. Lax AJ, Thomas W. How bacteria could cause cancer: one step at a time. Trends Microbiol. 2002;10:293–299.

Featured News

  • Monotheism in Medicine

    The following article by Dr. Manfred Doepp was published recently in the CO’MED journal under the column title of “Thoughts and Reflections”. Beyond its [...]

    June 15, 2010|Journal Translations|
  • Med-Tronik

    News, Gossip and Interesting Tidbits from the Med-Tronik Distributor’s Meeting Friesenheim, Germany October 29 & 30, 2010 There were nearly 40 of us as [...]

    December 15, 2010|Articles|
  • Tired of the Same Old CME?

    A Personal Message from Theodore (Ted) J. Cole, DO, NMD, Ohio, USA Crowded rooms, same old hotels, boring lectures. Are you ready for the [...]

    September 15, 2012|Commentaries & Editorials|
  • The Truth About the Flu Shot

    WEB WATCH Submitted by Esther Treitl, BC , Canada What’s in the regular flu shot? Egg proteins: including avian contaminant viruses Gelatin: can cause [...]

    February 15, 2010|Articles|

Sign-up to receive updates sent straight to your inbox