PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter

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.

► LY294002, a pharmacological PI3-kinase inhibitor directly inhibits ABCG2 function.
► Rapamycin, a pharmacological mTOR inhibitor directly inhibits ABCG2 function.
► LY294002 and rapamycin reverse ABCG2-mediated multidrug resistance.
► This phenomenon is independent from their effect on PI3K/Akt/mTOR signaling.
► Wortmannin, a pharmacological PI3-kinase inhibitor does not interact with ABCG2.