Abstract
This study aimed to establish a real-time monitoring system for evaluating the acid-producing activity of cells and the effects of microenvironmental pH on their metabolism. Oral squamous cell carcinoma (HSC-2, HSC-3) and normal (HaCaT) cells were used. Their acid-producing activity from glucose, glutamine, and glutamate was monitored at various pH values using a pH stat system. Their production of lactic acid and ammonia was also measured. The acid-producing activity was monitored successfully. Both the cancer and normal cells produced acids from glucose, glutamine, and glutamate. All of the cells decreased their acid-producing activity as the environmental pH fell, but in glucose-derived acid-producing activity the cancer cells were more acid-tolerant than HaCaT cells. In the cancer cells, the proportion of lactic acid among all acids produced from glucose at the acidic environment tended to be higher than that in HaCaT cells. All of the cells produced ammonia from glutamine, while only HaCaT cells produced ammonia from glutamate. We established a real-time monitoring system for evaluating the acid-producing activity of cells. Our results suggest that the cancer cells possess acid-tolerant glucose metabolism with a tendency of metabolic shift to lactic acid production at acidic pH and they metabolise glutamate without ammonia production.
Highlights
Many cancer-related genes, such as Myc and p53, have been reported[1, 2], and it has become clear that the metabolic activity of cancer cells is regulated by these oncogenes[3]
The relationships between environmental factors and cancer cells have been examined by many researchers, and it is becoming clear that environmental factors, such as acidic pH and low oxygen levels, are involved in the expression of genes, such as those encoding glucose transporter 1 and hexokinase II, through hypoxia-inducible factor-110, 11, and the inhibition of the tricarboxylic acid (TCA) cycle via the expression of pyruvate dehydrogenase
The glucose-derived acid-producing activity of the cancer cells was more acid-tolerant than that of the HaCaT cells significantly (Fig. 1B), while the glutamine-derived acid-producing activity was similar among all the cell type (Fig. 2B) and the glutamate-derived acid-producing activity of the cancer cells seemed to be more acid-sensitive than that of the HaCaT cells (Fig. 3B)
Summary
Many cancer-related genes, such as Myc and p53, have been reported[1, 2], and it has become clear that the metabolic activity of cancer cells is regulated by these oncogenes[3]. We have confirmed that oral squamous cell carcinoma (OSCC) cells demonstrate similar metabolic activity[7] These observations suggest that the pH of the microenvironment around cancer cells tends to change in response to the levels of acidic and alkaline metabolic products, such as lactic acid and ammonia. It was reported that a low pH microenvironment affected the permeability of a weakly alkaline drug and was associated with resistance to anticancer drugs[15] It remains unclear how environmental pH directly affects metabolic activity, probably because the biological activity of cancer cells has mainly been evaluated based on their proliferation potency in previous studies, and no method for the real-time monitoring of metabolic activity at a fixed pH has been developed. We attempted to establish a method for monitoring the acid-producing activity of cells in real time and to evaluate the direct effects of microenvironmental pH on the metabolic processes of cancer cells in comparison with normal cells
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