%0 Journal Article %A Paolo B. Abada %A Christopher A. Larson %A Gerald Manorek %A Preston Adams %A Stephen B. Howell %T Sec61β Controls Sensitivity to the Platinum Chemotherapeutic Agents Through Modulation of Copper-Transporting Atpase Atp7a %D 2012 %R 10.1124/mol.112.079822 %J Molecular Pharmacology %P mol.112.079822 %X The Sec61 protein translocon is a multimeric complex that transports proteins across lipid bilayers. We discovered that the Sec61β subunit modulates cellular sensitivity to chemotherapeutic agents, particularly the platinum drugs. To investigate the mechanism, expression of Sec61β was constitutively knocked down in 2008 ovarian cancer cells. Sec61β knockdown (KD) resulted in 8-, 16.8- and 9-fold resistance to cisplatin (cDDP), carboplatin, and oxaliplatin, respectively. Sec61β KD reduced the cellular accumulation of cDDP to 67% of the parental cells. Baseline copper (Cu), Cu uptake, and Cu cytotoxicity were also reduced. Given that Cu transporters and chaperones regulate Pt drug accumulation and efflux, their expression in 2008 Sec61β KD cells was analyzed and ATP7A was found to be 2 to 3-fold over-expressed while there was no change in ATP7B, ATOX1, CTR1, or CTR2. Cells lacking ATP7A did not exhibit increased cDDP resistance upon knockdown of Sec61β. Sec61β KD cells also exhibited altered ATP7A cellular distribution. We conclude that Sec61β modulates the cytotoxicity of many chemotherapeutic agents with the largest effect being on the platinum drugs. This is through its effect on the expression and distribution of ATP7A that has previously been shown to control Pt drug sequestration and cytotoxicity. %U https://molpharm.aspetjournals.org/content/molpharm/early/2012/06/18/mol.112.079822.full.pdf