Disruption of BASIGIN decreases lactic acid export and sensitizes non-small cell lung cancer to biguanides independently of the LKB1 status

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.

Prognostic significance of monocarboxylate transporter expression in oral cavity tumors

“…This fact was also observed in other types of cancers such as colon and ovary cancer, suggesting that MCT membrane expression in tumors may be depend on another regulatory protein, not yet identified. 46,47 MCT4 overall expression was significantly associated with higher T stage and TNM stages III/IV. A recent study analyzing MCT4 in HNSCC also obtained a significant association of MCT4 overall expression with bigger tumor size (T stage) and higher TNM staging.…”

A matrix‐assisted laser desorption ionization–time‐of‐flight–time‐of‐flight–mass spectrometry‐based toxicoproteomic screening method to assess in vitro particle potencies

“…These proteins are involved in cell proliferation, apoptosis, cell membrane transport, energy metabolism and inflammation‐related responses. (Granja et al, ; Kong et al, ; Li et al, ; Qi et al, ). Furthermore, these findings reveal that the observed proteomic changes are consistent with cytotoxicity results.…”

Value of pH regulators in the diagnosis, prognosis and treatment of cancer

“…For that reason, the role of MCTs in several cancer types, including expression analysis in human cancer tissues have been widely explored in the past years (for an extensive review see [16]). MCT1 and MCT4 are upregulated in tumour cells when compared to adjacent normal tissue in a variety of human malignancies including lung [17], breast [18], head and neck [19], renal [20], brain [21], adrenal [22], melanomas [23], pancreatic [24], colorectal [25], ovarian [26], bladder [27] and cervix [28]. Interestingly, in liver and prostate cancer, MCT1 appears downregulated, while MCT4 is upregulated [29,30].…”