Cancer cells exhibit a greatly increased level of aerobic glycolysis with accumulation of lactic acid, a phenomenon known as the Warburg effect. Apparently, survival of cancer cells requires an elaborate system for acid resistance. L-glutamine (Gln) has long been known to be essential for cancer cell growth, which is generally thought to relate to the nutritional value of Gln as carbon and nitrogen source. On the basis of our recent finding that Gln provides acid resistance for E. coli through release of ammonia, we hypothesized that the primary role of Gln in cancer cells is to fight acid, rather than provide nutrition, through enzymatic deamidation. In this letter, we provide preliminary experimental evidence that supports this hypothesis. We demonstrate that Gln helps cancer cells survive acidic stress, which is compromised by inhibition of specific glutaminase activity. Our data suggests that glutaminase inhibitors, currently under clinical trials as an anti-cancer drug, may work by countering the ability of cancer cells to survive under acidic environment. We further speculate that the general requirement of Gln in cell culture is also due to its crucial role in acid resistance.

A hallmark of cancer cell is described as the Warburg Effect, with increased aerobic glycolysis and reduced oxidative phosphorylation [1]. Even in the presence of oxygen, cancer cells convert glucose mainly into lactic acid, which, with a pK of 3.7, contributes to an acidic environment in tumor [2]. The extracellular pH value of human cancer tissues can be as low as 5.6 [3]. As numerous biological reactions are strictly pH dependent, lowered pH value may be detrimental to cancer cell growth. Consequently, cancer cells must be able to efficiently neutralize lactic acid to ensure normal growth. Supporting this analysis, the intracellular pH in tumors was reported to remain largely unchanged even when the extracellular pH value precipitously dropped as a consequence of cell growth [4]. This observation suggests presence of a robust acid resistance system within cancer cells. Much to our surprise, there is little description or research into the