Abstract
Abstract To further characterize the molecular basis on anticancer drug-resistance of human ovarian carcinoma, we compared glycolipid and transporter gene expressions in ovarian serous carcinoma-derived KF28 and 2008 cells with those in their paclitaxel- and cisplatin-resistant cells. Lipid compositions were determined by TLC and TLC-immunostaining and gene expressions of transporter proteins and glycosyltransferases were by RT-PCR. Although the amounts of major lipids, i.e. cholesterol, ceramides and phospholipids, in the resistant cells were same with those in the sensitive cells, Gb3Cer was commonly increased in all resistant cells, irrespective of whether the resistance was to paclitaxel or cisplatin. Also, expressions of the MDR1 gene and gangliosides, GM3 for KF28, and GM1 and GD1a for 2008 cells, were enhanced in paclitaxel-resistant cells, but gangliosides were absent in cisplatin-resistant cells. In accord with the decreased amounts of gangliosides in cisplatin-resistant cells, the gene expression and specific activity of GM3 synthase were greatly decreased in cisplatin-resistant cells. One can suggest that increased amount of Gb3Cer in cisplatin-resistant cells is brought about by the metabolic shifts of LacCer-modifying pathway from GM3- to Gb3Cer-synthases. Furthermore, paclitaxel- and cisplatin-resistant cells were converted to forms more sensitive to the respective anticancer drugs on cultivation with D-PDMP, an inhibitor of GlcCer synthase, and GM3, respectively, prior to the addition of anticancer drugs. Thus, coexpression of the MDR1 gene and glycolipids including gangliosides was thought to be necessary for survival of cells in media containing paclitaxel through regulation of transporter proteins with glycolipids in membrane rafts. Also, the decreased amounts of gangliosides might contribute to the cisplatin resistance, probably by the reduced incorporation of cisplatin. Citation Format: Kyoko Tanaka, Daisuke Aoki, Seiji Isonishi, Mikio Mikami, Kazushige Kiguchi, Masao Iwamori. Possible involvement of glycolipids in anticancer drug resistance of human ovarian serous carcinoma-derived cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2241. doi:10.1158/1538-7445.AM2013-2241
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