title: Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts.
abstract: A high incidence of relapses following induction chemotherapy is a major hindrance to patient survival in acute myelogenous leukemia (AML). There is strong evidence that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling network plays a significant role in rendering AML blasts drug resistant. An important mechanism underlying drug resistance is represented by overexpression of membrane drug transporters such as multidrug resistance-associated protein 1 (MRP1) or 170-kDa P-glycoprotein (P-gp). Here, we present evidence that MRP1, but not P-gp, expression is under the control of the PI3K/Akt axis in AML blasts. We observed a highly significant correlation between levels of phosphorylated Akt and MRP1 expression in AML cells. Furthermore, incubation of AML blasts with wortmannin, a PI3K pharmacological inhibitor, resulted in lower levels of phosphorylated Akt, downregulated MRP1 expression, and decreased Rhodamine 123 extrusion in an in vitro functional dye efflux assay. We also demonstrate that wortmannin-dependent PI3K/Akt inhibition upregulated p53 protein levels in most AML cases, and this correlated with diminished MRP1 expression and enhanced phosphorylation of murine double minute 2 (MDM2). Taken together, these data suggest that PI3K/Akt activation may lead to the development of chemoresistance in AML blasts through a mechanism involving a p53-dependent suppression of MRP1 expression.
authors.affiliation: Servizio di Immunoematologia e Trasfusionale, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: P L
authors.initials: PL
authors.lastname: Tazzari
authors.forename: A
authors.initials: A
authors.lastname: Cappellini
authors.forename: F
authors.initials: F
authors.lastname: Ricci
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.forename: V
authors.initials: V
authors.lastname: Papa
authors.forename: T
authors.initials: T
authors.lastname: Grafone
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
authors.forename: R
authors.initials: R
authors.lastname: Conte
authors.forename: L
authors.initials: L
authors.lastname: Cocco
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000494:pharmacology; D001859:Bone Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016158:Genes, p53; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D020112:Rhodamine 123 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D000077191:Wortmannin
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000730:Androstadienes; D005456:Fluorescent Dyes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D020112:Rhodamine 123; D016159:Tumor Suppressor Protein p53; D000077191:Wortmannin; C497206:MDM2 protein, human; C421109:multidrug resistance-associated protein 1