Nicotinamide N-methyltransferase enhances paclitaxel resistance in ovarian clear cell carcinoma

Abstract Background. Growing evidence suggests that nicotinamide N-methyltransferase (NNMT), an S-adenosyl-L-methionine (SAM)-dependent cytosolic enzyme, plays an essential role in cancer progression. Recently, it was reported that NNMT is involved in methylation metabolism and tumorigenesis and is associated with poor prognosis in a number of cancers. It has also been reported that NNMT is overexpressed in the stroma of advanced high-grade serous carcinomas and may contribute to poor survival. The aim of this study was to identify novel biomarkers that predict resistance in paclitaxel-resistant advanced or recurrent ovarian clear cell carcinoma (OCCA) and to evaluate their clinicopathologic significance. Methods. Four OCCA cell lines (ES-2, KK, OVMANA, and OVTOKO) were divided into paclitaxel high and low sensitivity groups by WST-8 assay and fluorescence-labeled two-dimensional electrophoresis (2D-DIGE) was performed. Protein spots with different expression intensities in each drug-sensitive group were analyzed by mass spectrometry to identify the proteins. Results. NNMT was detected as a protein molecule upregulated in the paclitaxel-resistant group, and knockdown by NNMT siRNA increased paclitaxel sensitivity in the NNMT-expressing ovarian clear cell carcinoma cell lines OVTOKO and RMG1. Furthermore, in analysis of clinical tissue samples, no deaths were observed in 7 patients with low NNMT expression in the cytoplasm of cancer cells. Conclusions. High NNMT expression in the cytoplasm of cancer cells is associated with low sensitivity to paclitaxel in OCCA and may have prognostic implications; knockdown of NNMT expression also reduced paclitaxel efficacy. Therefore, targeted therapies that reduce cytoplasmic NNMT expression levels may increase the sensitivity of OCCA to paclitaxel.