The block of the lactate transport and antidiabetic drugs inhibit tumor

Authors and Affiliations:

Sara Granja ^1,2, Ibtissam Marchiq ³, Renaud Le Floch ³, Conceição Souto Moura ^5,6, Fátima Baltazar ^1,2,* and Jacques Pouysségur ^3,4

¹ Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

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

³ Institute for Research on Cancer and Aging of Nice (IRCAN), Centre A. Lacassagne, Nice, France

⁴ Centre Scientifique de Monaco (CSM)

⁵ Department of Pathology, Centro Hospitalar de São João, Porto, Portugal

⁶ Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of University of Porto, Porto, Portugal

Abstract:

Most cancers rely on aerobic glycolysis to generate energy and metabolic intermediates. To maintain a high glycolytic rate, cells must efficiently export lactic acid through the proton-coupled monocarboxylate transporters (MCT1/4). These transporters require a chaperone, CD147/BASIGIN (BSG) for trafficking to the plasma membrane and function.

To validate the key role of these transporters in lung cancer, we first analysed the expression of MCT1/4 and BSG in 50 non-small lung cancer (NSCLC) cases. These proteins were specifically upregulated in tumour tissues. We then disrupted BSG in three NSCLC cell lines (A549, H1975 and H292) via ‘Zinc-Finger Nucleases’. The three homozygous BSG-/- cell lines displayed a low MCT activity (10- to 5-fold reduction, for MCT1 and MCT4, respectively) compared to wild-type cells. Consequently, the rate of glycolysis, compared to the wild-type counterpart, was reduced by 2.0- to 3.5-fold, whereas the rate of respiration was stimulated in BSG-/- cell lines. Both wild-type and BSG-null cells were extremely sensitive to the mitochondria inhibitor metformin/phenformin in normoxia. However, only BSG-null cells, independently of their LKB1 status, remained sensitive to biguanides in hypoxia in vitro and tumour growth in nude mice. Our results demonstrate that inhibiting glycolysis by targeting lactic acid export sensitizes NSCLC to phenformin.

Journal: Oncotarget

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2862