Premium
The human multidrug resistance P‐glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy
Author(s) -
Loo Tip W.,
Clarke David M.
Publication year - 1999
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.13.13.1724
Subject(s) - multiple drug resistance , p glycoprotein , lactacystin , cancer cell , chemotherapy , enzyme , drug resistance , cancer , biology , atp binding cassette transporter , cancer research , pharmacology , proteasome inhibitor , biochemistry , chemistry , transporter , proteasome , gene , genetics , microbiology and biotechnology
The human multidrug resistance P‐glycoprotein (P‐gp) contributes to the phenomenon of multidrug resistance during cancer and AIDS chemotherapy. A potential novel strategy to circumvent the effects of P‐gp during chemotherapy is to prevent maturation of P‐gp during biosynthesis so that the transporter does not reach the cell surface. Here we report that immature, core‐glycosylated P‐gp that is prevented from reaching the cell surface by processing mutations or by proteasome inhibitors such as lactacystin or MG‐132 exhibited no detectable drug‐stimulated ATPase activity. Disulfide cross‐linking analysis also showed that the immature P‐gp did not exhibit ATP‐induced conformational changes as found in the mature enzyme. In addition, the immature P‐gp was more sensitive to trypsin than the mature enzyme. These results suggest that P‐gp is unlikely to be functional immediately after synthesis. These differences in the structural and enzymatic properties of the mature and core‐glycosylated, immature P‐gp could potentially be used during chemotherapy, and should result in the search for compounds that can specifically inhibit the maturation of P‐gp.—Loo, T. W., Clarke, D. M. The human multi‐drug resistance P‐glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy. FASEB J . 13, 1724–1732 (1999)