Differential regulation of calcium homeostasis in adenocarcinoma cell line A549 and its Taxol‐resistant subclone

Abstract

Drug resistance is a fundamental problem in cancer chemotherapy. Intracellular calcium concentration ([Ca2+]i) may play a role in the development of chemoresistance. We investigated the regulatory role of [Ca2+]i in Taxol resistance in the non‐small‐cell lung cancer cell line A549 and its chemoresistant subclone A549‐T24. Measurement of cytosolic calcium ([Ca2+]c) in single cells and cell populations revealed similar levels of basal calcium in the two cell lines. However, a reduced response to thapsigargin (a sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) inhibitor) in A549‐T24 cells compared to the parent cell line suggested a lower ER Ca2+ content in these cells. mRNA expression of SERCA2b and SERCA3, major Ca2+ pumps involved in ER Ca2+ homeostasis, did not significantly differ between the two cell lines, as revealed by RT–PCR. An altered calcium influx pathway in the Taxol‐resistant cell line was observed. Modulation of the ER calcium pools using CMC (4‐chloro‐m‐cresol) and ATP revealed lower ryanodine receptor (RyR) and IP3 receptor (IP3R)‐sensitive Ca2+ stores in the chemoresistant cell line. Western blot and RT–PCR studies suggested that A549‐T24 cells expressed higher levels of the antiapoptotic protein Bcl‐2 and the calcium‐binding protein sorcin, respectively, in comparison to the parent cell line. Both of these proteins have been previously implicated in chemoresistance, in part, due to their ability to modulate [Ca2+]i. These results suggest that altered intracellular calcium homeostasis may contribute to the Taxol‐resistant phenotype. British Journal of Pharmacology (2004) 142, 305–316. doi:

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