title: PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter.
abstract: The ATP-binding cassette (ABC) transporter ABCG2 plays an important role in tissue detoxification and confers multidrug resistance to cancer cells. Identification of expressional and functional cellular regulators of this multidrug transporter is therefore intensively pursued. The PI3-kinase/Akt signaling axis has been implicated as a key element in regulating various cellular functions, including the expression and plasma membrane localization of ABCG2. Here we demonstrate that besides inhibiting their respective target kinases, the pharmacological PI3-kinase inhibitor LY294002 and the downstream mTOR kinase inhibitor rapamycin also directly inhibit ABCG2 function. In contrast, wortmannin, another commonly used pharmacological inhibitor of PI3-kinase does not interact with the transporter. We suggest that direct functional modulation of ABCG2 should be taken into consideration when pharmacological agents are applied to dissect the specific role of PI3-kinase/Akt/mTOR signaling in cellular functions.
authors.affiliation: Membrane Research Group of the Hungarian Academy of Sciences, Department of Biophysics, Semmelweis University and National Blood Center, Budapest, Hungary.
authors.forename: Csilla
authors.initials: C
authors.lastname: Hegedüs
authors.forename: Krisztina
authors.initials: K
authors.lastname: Truta-Feles
authors.forename: Géza
authors.initials: G
authors.lastname: Antalffy
authors.forename: Anna
authors.initials: A
authors.lastname: Brózik
authors.forename: Ildikó
authors.initials: I
authors.lastname: Kasza
authors.forename: Katalin
authors.initials: K
authors.lastname: Német
authors.forename: Tamás I
authors.initials: TI
authors.lastname: Orbán
authors.forename: Csilla
authors.initials: C
authors.lastname: Özvegy-Laczka
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077191:Wortmannin
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000077191:Wortmannin