Functional assay for plasma membrane transporter, MXR, and its clinical significance in urological cancer

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591699
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Kagoshima University
• Principal Investigator: NISHIYAMA Kenryu Kagoshima University, Graduate School of Medical and Dental Sciences, Assistant Professor, 大学院・医歯学総合研究科, 講師 (80264422)
• Co-Investigator(Kenkyū-buntansha): KUBO Hiroyuki Kagoshima University, Graduate School of Medical and Dental Sciences, Instructor Research Associate, 大学院・医歯学総合研究科, 助手 (60336344)
• Project Period (FY): 2003 – 2005
• Keywords: MXR / multidrug resistance / GS-X pump

Research Abstract

(1)Mutations at amino-acid 482 in the MXR gene contribute to the drug resistance profile and efficacy of MXR antagonists. As previously reported, membrane vesicles prepared from 482G-MXR-overexpressing MCF-7 AdVp3000 cells transport leukotrien C4 (LTC4) by ATP-dependent manner. Membrane vesicles from HEK-293 cells transfected with wild-type 482R or mutant 482G and 482T also transported LTC4. 482T membrane vesicles transported largest amount of LTC4. These data may indicate that the MXR is one of GS-X pumps and mutations at amino-acid 482 in the gene affect transporting activity for LTC4.
(2)ATP-dependent LTC4 transport by membrane vesicles from MCF7 AdVp3000cells was inhibited by novobiocin, MXR antagonist, but not by fumitremorgin C, another MXR antagonist. It is possible that these two drugs inhibit MXR by distinct manner. Further examination should be necessary.
3)We examined the expression of MXRmRNA by RT-PCR in 17 renal cell cancers from 16 patients. MXRmRNA was detected only 4 of 17 tissues, whereas MDR1mRNA and MRP1mRNA were positive for 10/17 and 13/17 tissues, respectively. Although an incidence of MXR expression in kidney cancer is low, this may indicate that MXR contribute to an intrinsic drug resistance in some RCCs. To examine expression profiles of ABC transporters including MXR could be a useful tool in selecting proper anti-cancer agents and antagonists.