科研之友
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摘要
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 CO2 export and generate HCO3- in the extracellular tumor space. It has been proposed that HCO3- is re-captured by the cell to maintain an alkaline pH(i). A diverse range of HCO3- 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+/HCO3- co-transporter (NBCe1) SLC4A4 mRNA expression exclusively in the LS174 colon adenocarcinoma cell line in a HIF1 dependent manner. HCO3- dependent pH(i) recovery observations revealed the predominant use of an NBC mechanism suggesting that reversal of a Cl-/HCO3- 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+/HCO3- 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 HCO3- transport and tumor cell phenotype. This study complements the on-going molecular characterization of the HCO3- re-uptake mechanism in other tumor cells for future strategies targeting these potentially important drug targets. J. Cell. Physiol. 230: 1954-1963, 2015.
- 出版日期2015-8
