Loss of expression of a new member of the DNAJ protein family confers resistance to chemotherapeutic agents used in the treatment of ovarian cancer

Differential display-PCR between ovarian tumor cell lines and shortterm cul tures of normal ovarian epithelial cell brushings was used to isolate a dif ferentially expressed transcript and its corresponding gene. The gene, whic h mapped to 13q14.1, has partial homology in the DNAJ domain to a number of proteins with a similar domain and was designated as methylation-controlle d J protein (MCJ), MCJ has the highest similarity to a functionally undefin ed protein from Caenorhabditis elegans. MCJ is expressed as a 1.2-kb transc ript in several adult tissues, with testis showing the highest level of exp ression. Expression of MCJ was absent in three of seven ovarian cancer cell lines. Similarly, expression analysis using semiquantitative reverse trans cription-PCR indicated that 12 of 18 primary ovarian tumors examined had ei ther a complete absence or lower levels of expression of this gene. 5-Aza-2 ' -deoxycytidine treatment of the OV202 cell line induced MCJ expression i n a dose-dependent manner, implicating methylation in this induction. Loss of heterozygosity and methylation-specific PCR analysis revealed that the l oss of MCJ expression in primary tumors and cell lines was attributable to deletion of one allele and methylation of the other. To assess the potentia l functional significance of MCJ down-regulation, the sensitivity of parent al (MCJ-nonexpressing) and MCJ-transfected OV167 cells to antineoplastic ag ents was evaluated. MCJ expression was associated with enhanced sensitivity to paclitaxel, topotecan, and cisplatin, suggesting that MCJ loss may play a role in de novo chemoresistance in ovarian carcinoma. These observations raise the possibility that MCJ loss may: (a) have potential prognostic sig nificance in ovarian cancer; and (b) contribute to the malignant phenotype by conferring resistance to the most commonly used chemotherapeutic agents for ovarian cancer.