Wednesday, February 01, 2017

Scientific publication in Medical Biology - Hypoxia and tumour metabolism team

Genetic validation of anti-cancer targets that regulate intracellular pH: carbonic anhydrases and Na+/H+ exchangers

Cells require energy to enable growth and specialised functions. This energy is obtained via two metabolic pathways that utilise nutritional elements within the blood (sugar, amino acids, lipids):

  1. Oxidative metabolism which occurs in the mitochondria to produce ATP (the form of ‘energy’ used by cells) and CO2 (carbonic acid) as a metabolic waste product;
  2. Fermentative glycolytic metabolism transforming glucose into lactic acid within the cytoplasm.

The most aggressive tumour cells use predominantly the fermentative pathway (2) and this exacerbated glycolytic metabolism (Warburg effect) results in a substantial lactic acidosis within the tumour microenvironment. As glycolytic metabolism is extremely sensitive to changes in intracellular pH (pHi), we proposed that blocking transporters involved in either H+ or CO2 secretion (carbonic anhydrase) (Figure 1) would have a major anti-cancer impact. Major limitations exist in the availability and specificity of inhibitors for the multitude of these transporters. Therefore we have approached this question via specifically disrupting these genes of interest using two targeted genetic editing techniques: ZFNs and CRISPR-Cas9.

© CSM
Figure 1: Schematic representation of the major proteins involved in the regulation of intracellular pH (pHi). Carbonic anhydrase IX (CA9) induced by hypoxia (HIF) catalyses the extracellular hydration of CO2 into HCO3- and H+. Its activity accelerates the export of CO2 and contributes to the maintenance of an alkaline intracellular compartment. MCT4 is another transporter, also induced by HIF actively implicated in the export lactic acid. NHE1 is the Na+/H+ activated by the Na+ gradient to assure the homeostasis of intracellular pH.

 

The article published in December 2016 in the international journal ‘Oncotarget’ demonstrates that the invalidation of either the Na+/H+-exchanger 1 (NHE1-ko), or the carbonic anhydrase 9 (CA9-ko), a gene that is induced by hypoxia in tumours and results in a very poor prognosis for patients, strongly reduces tumour growth (Figure 2).

These results validate without question the importance of pH regulation in tumour development. In addition, the 90% reduction of human lung and tumour growth by single invalidation of CA9 enforces the ‘Darwinian characteristic’ of the epigenetic expression of CA9. 

© CSM
Figure 2 : Tumour growth in immunocompromised mice. Specific disruption of the genes encoding either the Na+/H+-exchanger (NHE1) or the carbonic anhydrase IX (CA9) reduce tumour growth by 75-90% respectively.
 
 

Parks, S.K., Cormerais, Y., Durivault, J. and Pouyssegur, J. (2016) 'Genetic disruption of the pHi-regulating proteins Na+/H+ exchanger 1 (SLC9A1) and carbonic anhydrase 9 severely reduces growth of colon cancer cells'. LID - 10.18632/oncotarget.14379 [doi]. Oncotarget (1949-2553 (Electronic)).

 
 
Research funded by CSM with GEMLUC support.
 
 

For more information, refer to www.centrescientifique.mc or contact :

- Dr. Scott ParksPost-doctoral scientist in the team 'Hypoxia and tumour metabolism', Medical Biology Department, Centre Scientifique de Monaco. (sparks@centrescientifique.mc)

- Dr. Jacques PouysségurTeam leader 'Hypoxia and tumour metabolism', Medical Biology Department, Centre Scientifique de Monaco  (Jpouyssegur@centrescientifique.mc)

 

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