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Calreticulin Expression Is Associated with Androgen Regulation of the Sensitivity to Calcium Ionophore-induced Apoptosis in LNCaP Prostate Cancer Cells¹

Departments of Urology [N. Z., Z. W.] and Molecular Pharmacology and Biological Chemistry [Z. W.] and The Robert H. Lurie Cancer Center [Z. W.], Northwestern University Medical School, Chicago, Illinois 60611

Calreticulin has been identified previously as one of the androgen-response genes in the prostate. The role of calreticulin in androgen action was studied using androgen-sensitive LNCaP and androgen-insensitive PC-3 human prostate cancer cell lines. Calreticulin appears to be a primary androgen-response gene in cultured LNCaP cells because androgen induction of calreticulin mRNA resists protein synthesis inhibition. Calreticulin is a high capacity intracellular Ca²⁺ binding protein, suggesting that calreticulin expression is likely to be associated with the intracellular Ca²⁺ buffering capacity that could regulate the sensitivity to cytotoxic intracellular Ca²⁺ overload. As expected, androgen protects androgen-sensitive LNCaP but not androgen-insensitive PC-3 cells from cytotoxic intracellular Ca²⁺ overload induced by Ca²⁺ ionophore A23187. To provide evidence for the role of calreticulin in reducing cytotoxic effect of Ca²⁺ influx in prostatic cells, we have shown that calreticulin antisense oligonucleotide down-regulates calreticulin protein level and significantly increases the sensitivity to A23187-induced apoptosis in both LNCaP and PC-3 cells. Furthermore, calreticulin antisense oligonucleotide reverses the androgen-induced resistance to A23187 in LNCaP cells. The above observations collectively suggest that calreticulin mediates androgen regulation of the sensitivity to Ca²⁺ ionophore-induced apoptosis in LNCaP cells.

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