Alterations in Ca²⁺ transport ATPase and P-glycoprotein expression can mediate resistance to thapsigargin

Resistance to the intracellular Ca²⁺ pump inhibitor thapsigargin (TG) is associated with overexpression of both Ca²⁺ transport ATPase and the multidrug resistance (mdr) transporter P-glycoprotein (pgp). This is supported by increased resistance to TG following transfection of a functional pgp1 cDNA, and reversal of TG resistance with known inhibitors of pgp function. However, pgp is unlikely to represent the only mechanism of resistance to TG. Cell lines selected for high levels of resistance to TG (250-fold) show only a 3.7-fold increase in pgp expression and a 2-fold increase in cross-resistance to other drugs of the mdr class. Overexpression of endogenous Ca²⁺ transport ATPase may represent a second mechanism of resistance to TG. Increased Ca²⁺ ATPase expression (3-fold) is seen in cells made resistant to TG, and TG resistance increases with the transfection of a specific Ca²⁺ ATPase cDNA into DC-3F cells. If these transfectants are then made resistant to TG, both the endogenous Ca²⁺ ATPase and the exogenously transfected Ca²⁺ ATPase become overexpressed. These studies suggest that while TG may be a substrate for pgp, acquired resistance to TG can involve alterations in both pgp and Ca²⁺ATPaSe expression. Additional, as yet unidentified, mechanisms of resistance may be involved in resistance to TG.