TY - JOUR T1 - Copper Transporter 2 (CTR2) regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.110.068411 SP - mol.110.068411 AU - Brian G Blair AU - Christopher A Larson AU - Preston L Adams AU - Paolo B Abada AU - Catherine E Pesce AU - Roohangiz Safaei AU - Stephen Howell Y1 - 2010/10/07 UR - http://molpharm.aspetjournals.org/content/early/2010/10/07/mol.110.068411.abstract N2 - Copper transporter 2 (CTR2) is one of the four copper transporters in mammalian cells that influence the cellular pharmacology of cisplatin and carboplatin. CTR2 was knocked down using an shRNAi. Robust expression of CTR2 was observed in parental tumors grown in vivo whereas no staining was found in the tumors formed from cells in which CTR2 had been knocked down. Knockdown of CTR2 reduced growth rate by 5.8-fold, increased the frequency of apoptotic cells and decreased the vascular density, but did not change copper content. Knockdown of CTR2 increased the tumor accumulation of cisplatin by 9.1-fold and greatly increased it therapeutic efficacy. As altered endocytosis has been implicated in cDDP resistance, uptake of dextran was used to quantify the rate of macropinocytosis. Knockdown of CTR2 increased dextran uptake by 2.0-fold without reducing exocytosis. Inhibition of macropinocytosis with either amiloride or wortmannin blocked the increase in macropinocytosis mediated by CTR2 knockdown. Stimulation of macropinocytosis by PDGF coordinately increased dextran and cDDP uptake. Knockdown of CTR2 was associated with activation of the Rac1and cdc42 GTPases that control macropinocytosis but not activation of the phosphoinositide-3 kinase pathway. We conclude that CTR2 is required for optimal tumor growth and that it is an unusually strong regulator of cisplatin accumulation and cytotoxicity. CTR2 regulates the transport of cDDP in part through control of the rate of macropinocytosis via activation of Rac1 and cdc2. Selective knockdown of CTR2 in tumors offers a strategy for enhancing the efficacy of cDDP. ER -