The Na + /HCO 3 − Co‐Transporter SLC4A4 Plays a Role in Growth and Migration of Colon and Breast Cancer Cells

The hypoxic and acidic tumor environment necessitates intracellular pH (pH i ) regulation for tumor progression. Carbonic anhydrase IX (CA IX; hypoxia‐induced) is known to facilitate CO 2 export and generate HCO 3 − in the extracellular tumor space. It has been proposed that HCO 3 − is re‐captured by the cell to maintain an alkaline pH i . A diverse range of HCO 3 − transporters, coupled with a lack of a clear over‐expression in cancers have limited molecular identification of this cellular process. Here, we report that hypoxia induces the Na + /HCO 3 − co‐transporter (NBCe1) SLC4A4 mRNA expression exclusively in the LS174 colon adenocarcinoma cell line in a HIF1α dependent manner. HCO 3 − dependent pH i recovery observations revealed the predominant use of an NBC mechanism suggesting that reversal of a Cl − /HCO 3 − exchanger is not utilized for tumor cell pH i regulation. Knockdown of SLC4A4 via shRNA reduced cell proliferation and increased mortality during external acidosis and spheroid growth. pH i recovery from acidosis was partially reduced with knockdown of SLC4A4. In MDA‐MB‐231 breast cancer cells expressing high levels of SLC4A4 compared to LS174 cells, SLC4A4 knockdown had a strong impact on cell proliferation, migration, and invasion. SLC4A4 knockdown also altered expression of other proteins including CA IX. Furthermore the Na + /HCO 3 − dependent pH i recovery from acidosis was reduced with SLC4A4 knockdown in MDA‐MB‐231 cells. Combined our results indicate that SLC4A4 contributes to the HCO 3 − transport and tumor cell phenotype. This study complements the on‐going molecular characterization of the HCO 3 − re‐uptake mechanism in other tumor cells for future strategies targeting these potentially important drug targets. J. Cell. Physiol. 230: 1954–1963, 2015. © 2015 Wiley Periodicals, Inc.