Overexpression of sorcin, a calcium-binding protein, induces a low level of paclitaxel resistance in human ovarian and breast cancer cells

Paclitaxel, an antimitotic, anticancer agent, induces cell cycle arrest in the mitotic phase by binding to the beta-tubulin subunit and forming highly stable microtubule polymers that resist de polymerization. The overexpression of the P-glycoprotein (P-gp) and/or alteration in the cellular microtubules is associated with the development of pactitaxel resistance, However, we have established a paclitaxel-resistant human ovarian carcinoma subline (2008/I3/4) wherein the degree of resistance could not be correlated with overexpression of P-gp, alterations in the alpha- and beta-tubulin isotypes, or changes in the drug-binding affinity of the microtubules. mRNA differential display analysis revealed the overexpression of sorcin, a calcium-binding protein in the 2008/13/4 cells. However, no detectable changes in the intracellular calcium levels were detected in the parental and the paclitaxel-resistant variant. Furthermore, co-treatment with A23187, a calcium ionophore. did not alter the cytotoxicity of paclitaxel against the parental and the paclitaxel-resistant cells. Transfection of the parental 2008 cells with full-length sorcin cDNA induced a low level (3-5-fold) of paclitaxel resistance, In addition, transfection of human breast cancer cells with the full-length sorcin cDNA also led to the induction of a low level of paclitaxel resistance in the transfectants. Although the overexpression of sorcin did not produce high levels of paclitaxel resistance, the results obtained present compelling evidence of the involvement of sorcin in developing low-level paclitaxel resistance in a variety of tumor cells, The precise biochemical mechanism(s) by which sorcin overexpression induces low-level paclitaxel resistance is currently under investigation. (C) 2002 Elsevier Science Inc. All rights reserved.