The identification of genes related to the sensitivity against anti-cancer drug, and application for clinical treatment

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To investigate the molecules that regulate the acquisition of cis-diamminedichloroplatinum(II)(cisplatin)-resistance, we performed cDNA microarrays using two pairs of parental and its cisplatin-resistant bladder cancer cell lines. We found a markedly reduced expression of Inositol 1,4,5-trisphosphate(IP_3) receptor type1(IP_3R1), endoplasmic reticulum(ER) membrane protein, in cisplatin-resistant cells. We also observed the induction of ER stress by cisplatin, which was accompanied by the phosphorylation of α-subunit of eukaryotic translation initiation factor 2(eIF-2α) only in the parental cell lines but not in resistant cell lines. The suppression of IP_3R1 expression using small interfering RNA(siRNA) in parental cells prevented eIF-2α phosphorylation and apoptosis, and resulted in decreased sensitivity to cisplatin. Oppositely, overexpression of IPs_3R1 in resistant cells induced eIF-2α phosphorylation and apoptosis, and increased sensitivity to cisplatin. These results suggest that cisplatin-induced downregulation of IP_3R1 expression was closely associated with the sensitivity of cisplatin via ER stress in bladder cancer cells. Further analyses of IP_3R1 expression level in patients before or after cisplatin treatment are presently in progress to confirm these findings. IP_3R1 could be a good molecular marker to predict cisplatin sensitivity and be a therapeutical molecular target of cisplatin in future.