Increased expression of cdc2 inhibits transport function of RLIP76 and promotes apoptosis.
RLIP76 is a stress-responsive glutathione-electrophile-conjugates (GS-E) and drugs transporter which is over-expressed in different types of cancers. Cdc2 is a cell-cycle check point control kinase which has been shown to bind to RLIP76 during mitosis, such that endocytosis is inhibited. In present studies, we have purified cdc2 and examined its effect on the transport activity of RLIP76 reconstituted into artificial liposomes. Both doxorubicin (DOX) and dinitro-phenyl S-glutathione (DNP-SG) transport were inhibited by cdc2 in a concentration dependent manner. Liposomal delivery of cdc2 to H358 cells caused apoptosis, resulted in an increased intracellular doxorubicin-accumulation and decreased rate of efflux from the cells. In the present communication, we propose that the accumulation-deficient drug-resistance mediated by RLIP76 can be modulated by inhibition of RLIP76 transport activity by cdc2.
Department of Molecular Biology and Immunology, 3500 Camp Bowie Blvd., University of North Texas Health Science Center, Fort Worth, TX 76107-2699, United States. ssinghal@hsc.unt.edu
Sharad S
SS
Singhal
Sushma
S
Yadav
Rit
R
Vatsyayan
Pankaj
P
Chaudhary
Jozef
J
Borvak
Jyotsana
J
Singhal
Sanjay
S
Awasthi
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000096:biosynthesis*; D018844:Cyclin-Dependent Kinases; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008081:Liposomes; D021381:Protein Transport / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D019926:Cyclin B; D020690:GTPase-Activating Proteins; D008081:Liposomes; C095637:RALBP1 protein, human; D004317:Doxorubicin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D005978:Glutathione