Lymphoma cell


Cancer cells: the initial step to the dark side

By Juman Hijab

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Original date: March 19, 2023  

Updated: June 28, 2023

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Lymphoma cell

David A Litman. Lymph node from a patient with Hodgkin's Disease (lymphoma), showing a Reed Sternberg cell variant., Stock Photo ID: 1012664833.

Cancer cells have gone to the dark side of cellular metabolism

When I think of creatures that are metabolically very active, I think of creatures with very fast heart rates, like mice, hamsters, and hummingbirds (450-750 bpm, 300-600 bpm, and  500-1,200 bpm, respectively). In these animals, there is no dark side of cellular metabolism. 

On the other hand, when you take cancer cells, they have a high metabolic rate that seems to be geared to the dark side: the task of perpetually dividing regardless of the needs of the organism. Cancer cells are active 24/7 and don't take a break.

In this article, I discuss one of the earliest steps in the metabolic foray of cancer cells to the dark side.

Incredibly effective at glucose uptake

If you keep on feeding a normal cell 24/7 with glucose; it would become saturated with glycogen. However, when there is no glucose, the cell reverses its cellular processes to break down glycogen and produce glucose. This is a healthy circular feedback loop: Lots of glucose --> Glycogen; no glucose --> Breakdown glycogen.

Cancer cells are highly adept at taking up glucose (1234). There are multiple glucose transporters in the plasma membranes; those proteins are over-expressed in cancer cells. But, in contrast to normal cells, cancer cells don't store glucose as glycogen. Their whole system is geared to take up glucose and shuttle it to the production of proteins and nucleic acids. They process all the "food" that they ingest to produce another cancer cell. 

What drives this insanity? Why are the normally circular glucose pathways uni-directional? 

Excess production of lactate

One proposal is that the cell is starved for acid ions (H+) (1, 5, 6).

Cancer cells' primary abnormality may be that they are too efficient at getting protons out of the cell. This makes the pH in the cytoplasm alkaline. In fact, cancer cells are known to have an unusually alkaline pH when compared to non-cancerous cells (cytoplasmic pH 7.12-7.7 vs 6.99-7.05, respectively).  

This high - or alkaline - pH in the cytoplasm stimulates the enzymes that break down glucose (glycolysis). In particular, rate-limiting enzymes in glycolysis such as phosphofructokinase are 100 times more active when the pH is more alkaline (1, 5).

The cell heeds the call of an alkaline pH and starts furiously breaking down glucose into lactic acid to bring the pH to a more acidic level.

An akaline pH and a move to the dark side of cellular metabolism

However, as I noted, cancer cells are adept at getting rid of H+ to the extracellular space. They have a superabundance of proton-removal machinery, like the Na/H+ exchanger (NHE1 - 15) ). This creates an unfortunate duality: a highly acidic extracellular space, while the cytoplasm is alkaline.

Lactate transporters need  the proton ions to efficiently transport lactate out of the cell. Some of the lactate is shuttled out, but the extra lactate in the cell has to go somewhere. To prevent the gridlock, the cells shuttle the breakdown products of glucose into other avenues. Those products are shuttled into other systems - like the Pentose Phosphate Pathway (PPP). This leads to the formation of nucleic acids (6, 7).

To add insult to injury, many of the enzymes in the PPP system  are also more active in an alkaline environment. Thus, an alkaline environment perpetuates the dark side of cellular metabolism:

  • A hyper-active glycolytic system to produce more protons (which are unfortunately quickly kicked out of the cell) 
  • shuttling of glucose by-products into revving up  the nuclear machinery.

To prove this thesis (the power of changing the pH in the cytoplasm to an alkaline level and its effect on the cell), there have been multiple studies that have shown that: 

  • the first step in malignant transformation of normal cells is the activation of the proton exchangers (like NHE1).
  • This is followed by cytosplasmic alkalinization (1, 5).
  • The increase in the cytoplasmic pH is followed by an increase in glycolytic pathways (5). 

Hypoxia and high intracellular pH both induce malignant transformation

Interestingly, hypoxia has exactly the same effect on cells as an alkaline cytoplasmic pH. With hypoxia, the cell moves into anaerobic glycolysis (breakdown of glucose without oxygen). The net result is the same.

The cell overproduces lactic acid, the extracellular space becomes acidic, and the cell pushes the intermediate metabolites from the breakdown of glucose into other pathways.

In fact, chronic hypoxia is enough to induce malignant transformation in cells . Thus, both oncogenes and hypoxia seem to promote the systems that create a rise in cytoplasmic pH as an early step in the malignant transformation process (5).

Unfortunately, in the cancer evolution, tissue hypoxia develops as the mass of tumor cells has a dysfunctional microcirculation. Not only do cancer cells have internal dysregulation of their metabolism (with the alkaline pH); their extracellular space - with an acidic pH and a hypoxic milieu - perpetuates ongoing production of glucose breakdown products, which further exacerbates the cancer pathology (8, 9, 10, 11, 12, 13, 14).


The pH homeostasis of a cell is one of the most important signals of health (15). Normal cells and their enzymes have well-defined ranges of acidity or alkalinity for optimal activity.  

Clearly, when the cytoplasmic pH range is abnormally high, cancer can develop. A major reason for this is that the enzymes that are trying to correct the alkaline pH are more active in alkaline pH ranges. That makes perfect sense, except that those enzymes rev up the metabolism of the cell to generate more protons but to no avail: the enzymes cannot successfully fill a leaky cytoplasmic bucket with enough protons.

Thus, over-expression of proteins that keep the pH high in the cytoplasm perpetuates the pathology and is a clear promoter of the cancer phenotype.


  1. Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Adil HH, Elhassan GO, Ibrahim ME, David Polo Orozco J, Cardone RA, Reshkin SJ, Harguindey S. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience. 2014 Dec 18;1(12):777-802. doi: 10.18632/oncoscience.109. Erratum in: Oncoscience. 2015;2(4):317. PMID: 25621294; PMCID: PMC4303887.
  2. Liu C, Jin Y, Fan Z. The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer. Front Oncol. 2021 Sep 3;11:698023. doi: 10.3389/fonc.2021.698023. PMID: 34540667; PMCID: PMC8446599.
  3. Yin C, Qie S, Sang N. Carbon source metabolism and its regulation in cancer cells. Crit Rev Eukaryot Gene Expr. 2012;22(1):17-35. doi: 10.1615/critreveukargeneexpr.v22.i1.20. PMID: 22339657; PMCID: PMC4505802.
  4. Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016 Nov 8;15(1):69. doi: 10.1186/s12943-016-0555-x. PMID: 27825361; PMCID: PMC5101698.
  5. Harguindey S, Arranz JL, Polo Orozco JD, Rauch C, Fais S, Cardone RA, Reshkin SJ. Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs--an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research. J Transl Med. 2013 Nov 6;11:282. doi: 10.1186/1479-5876-11-282. PMID: 24195657; PMCID: PMC3826530. 
  6. Alfarouk KO, Ahmed SBM, Elliott RL, Benoit A, Alqahtani SS, Ibrahim ME, Bashir AHH, Alhoufie STS, Elhassan GO, Wales CC, Schwartz LH, Ali HS, Ahmed A, Forde PF, Devesa J, Cardone RA, Fais S, Harguindey S, Reshkin SJ. The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH. Metabolites. 2020 Jul 11;10(7):285. doi: 10.3390/metabo10070285. PMID: 32664469; PMCID: PMC7407102.
  7. Cho ES, Cha YH, Kim HS, Kim NH, Yook JI. The Pentose Phosphate Pathway as a Potential Target for Cancer Therapy. Biomol Ther (Seoul). 2018 Jan 1;26(1):29-38. doi: 10.4062/biomolther.2017.179. PMID: 29212304; PMCID: PMC5746035.
  8. Harguindey S, Stanciu D, Devesa J, Alfarouk K, Cardone RA, Polo Orozco JD, Devesa P, Rauch C, Orive G, Anitua E, Roger S, Reshkin SJ. Cellular acidification as a new approach to cancer treatment and to the understanding and therapeutics of neurodegenerative diseases. Semin Cancer Biol. 2017 Apr;43:157-179. doi: 10.1016/j.semcancer.2017.02.003. Epub 2017 Feb 11. PMID: 28193528.
  9. McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G, Nemirovsky O, Gillespie JA, Karasinska JM, Kalloger SE, Supuran CT, Schaeffer DF, Bashashati A, Shah SP, Topham JT, Yapp DT, Li J, Renouf DJ, Stanger BZ, Dedhar S. Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. Gastroenterology. 2019 Sep;157(3):823-837. doi: 10.1053/j.gastro.2019.05.004. Epub 2019 May 9. PMID: 31078621.
  10. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010 Sep 17;329(5998):1492-9. doi: 10.1126/science.1188015. PMID: 20847263; PMCID: PMC3030121.
  11. Belisario DC, Kopecka J, Pasino M, Akman M, De Smaele E, Donadelli M, Riganti C. Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance. Cells. 2020 Dec 4;9(12):2598. doi: 10.3390/cells9122598. PMID: 33291643; PMCID: PMC7761956.
  12. Alfarouk KO, Ahmed SBM, Ahmed A, Elliott RL, Ibrahim ME, Ali HS, Wales CC, Nourwali I, Aljarbou AN, Bashir AHH, Alhoufie STS, Alqahtani SS, Cardone RA, Fais S, Harguindey S, Reshkin SJ. The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer. Cancers (Basel). 2020 Apr 7;12(4):898. doi: 10.3390/cancers12040898. PMID: 32272658; PMCID: PMC7226178.
  13. Jiang B. Aerobic glycolysis and high level of lactate in cancer metabolism and microenvironment. Genes Dis. 2017 Feb 14;4(1):25-27. doi: 10.1016/j.gendis.2017.02.003. PMID: 30258905; PMCID: PMC6136593.
  14. Pethő Z, Najder K, Carvalho T, McMorrow R, Todesca LM, Rugi M, Bulk E, Chan A, Löwik CWGM, Reshkin SJ, Schwab A. pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology. Cancers (Basel). 2020 Sep 2;12(9):2484. doi: 10.3390/cancers12092484. PMID: 32887220; PMCID: PMC7565548.
  15. Silverstein TP. The Proton in Biochemistry: Impacts on Bioenergetics, Biophysical Chemistry, and Bioorganic Chemistry. Front Mol Biosci. 2021 Nov 26;8:764099. doi: 10.3389/fmolb.2021.764099. PMID: 34901158; PMCID: PMC8661011.


cancer, cells, lactic acid, pH

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