PH regulators as markers of diagnosis, prognosis and therapeutic targets in cancer

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PH regulators as markers of diagnosis, prognosis and therapeutic targets in cancer

Wednesday, 08.02.2017

Most tumor cells depend on glucose for energy production and cellular building blocks needed for cell proliferation. However, most of the glucose consumed is transformed in lactic acid, which is then exported out of the cell, acidifying the extracellular medium. This tumor acidity is associated with higher aggressiveness, as well as with resistance to therapy. Cancer cells are able to survive in this acidic environment due to the function of proteins that regulate their pH, which expression in increased in several types of tumors. Thus, these proteins constitute important and promissing targets for cancer therapy and inhibitors of these molecules have been used successfully in experimental models, and some of them are already being tested in humans.

The aim of this work was to review the main studies exploring these pH regulators as markers of diagnosis and prognosis, as well as their exploitation as therapeutic targets in several types of cancer.

 

Authors and Affiliations:

Sara Granja1,2*; Diana Tavares-Valente1,2,3*; Odília Queirós3,4*; Fátima Baltazar1,2*#

1 Life and Health Sciences Research Institute (ICVS)/ School of Medicine/ University of Minho, Campus de Gualtar, Braga, 4710-057, Portugal;

2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal;

3 IINFACTS - Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal;

4 CBMA - Center of Molecular and Environmental Biology/Department of Biology/University of Minho, Campus de Gualtar, Braga, 4710-057, Portugal.

 

* The authors contributed equally to this work

 

Abstract:

Altered metabolism, associated with acidification of the extracellular milieu, is one of the major features of cancer. As pH regulation is crucial for the maintenance of all biological functions, cancer cells rely on the activity of lactate exporters and proton transporters to regulate their intracellular pH. The major players in cancer pH regulation are proton pump ATPases, sodium-proton exchangers (NHEs), monocarboxylate transporters (MCTs), carbonic anhydrases (CAs) and anion exchangers (AEs), which have been shown to be upregulated in several human malignancies. Thanks to the activity of the proton pumps and transporters, tumours acidify their microenvironment, becoming more aggressive and resistant to therapy. Thus, targeting tumour pH may contribute to more effective anticancer strategies for controlling tumour progression and therapeutic resistance. In the present study, we review the role of the main pH regulators expressed in human cancer cells, including their diagnostic and prognostic value, as well as their usefulness as therapeutic targets.

 

Journal:Seminars in Cancer Biology

 

Link: http://www.sciencedirect.com/science/article/pii/S1044579X16300815