DEPLETION OF INTRACELLULAR CA2-ALPHA, AND SUSTAINED INHIBITION OF TRANSLATION INITIATION MEDIATE THE ANTICANCER EFFECTS OF CLOTRIMAZOLE( STORES, PHOSPHORYLATION OF EIF2)

Regulation of translation initiation plays a critical role in the cont rol of cell growth and division in eukaryotic cells. Translation of ma ny growth regulatory proteins including cyclins depends critically on translation initiation factors because their mRNAs are translated inef ficiently, We report that clotrimazole, a potent antiproliferative age nt both in vitro and in vivo, inhibits cell growth by interfering with translation initiation. In particular, clotrimazole causes a sustaine d depletion of intracellular Ca2+ stores, which results in activation of PKR, phosphorylation of eIF2 alpha, and thereby in inhibition of pr otein synthesis at the level of translation initiation, Consequently, clotrimazole preferentially decreases the expression of the growth pro moting proteins cyclin A, E and D1, resulting in inhibition of cyclin- dependent kinase activity and blockage of cell cycle in G(1).