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The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases (CA) IX and CAXII constitute a robust intracellular pH (pH i )-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX) and LS174Tr cells (inducible knock-down for  ca9 / ca12 ) were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pH o  manipulations and hypoxia (1% O 2 ) exposure. Radiotherapy was used to target  ca9/ca12 -silenced LS174Tr tumors grown in  nude  mice. We found that diminishing the pH i -regulating capacity of fibroblasts through inhibition of Na + /H +  exchanger 1 sensitize cells to radiation-induced cell death. Secondly, the pH i -regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either  ca9  or both  ca9 / ca12 , showed a respective 50 and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pH i  regulation. Finally, LS174Tr tumor progression was strongly decreased when  ca9 / ca12  silencing was combined with irradiation  in vivo . These findings highlight the combinatory use of radiotherapy with targeting of the pH i -regulating CAs as an anti-cancer strategy.

Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis