title: Inhibition of tumor cell growth by Sigma1 ligand mediated translational repression.
abstract: Treatment with sigma1 receptor (Sigma1) ligands can inhibit cell proliferation in vitro and tumor growth in vivo. However, the cellular pathways engaged in response to Sigma1 ligand treatment that contribute to these outcomes remain largely undefined. Here, we show that treatment with putative antagonists of Sigma1 decreases cell mass. This effect corresponds with repressed cap-dependent translation initiation in multiple breast and prostate cancer cell lines. Sigma1 antagonist treatment suppresses phosphorylation of translational regulator proteins p70S6K, S6, and 4E-BP1. RNAi-mediated knockdown of Sigma1 also results in translational repression, consistent with the effects of antagonist treatment. Sigma1 antagonist mediated translational repression and decreased cell size are both reversible. Together, these data reveal a role for Sigma1 in tumor cell protein synthesis, and demonstrate that small molecule Sigma1 ligands can be used as modulators of protein translation.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102-1192, USA. fkim@drexelmed.edu
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Kim
authors.forename: Joel M
authors.initials: JM
authors.lastname: Schrock
authors.forename: Christina M
authors.initials: CM
authors.lastname: Spino
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Marino
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D048429:Cell Size / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009025:Morpholines / Q000494:pharmacology; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D039381:RNA Cap-Binding Proteins / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D006220:Haloperidol; D008024:Ligands; D009025:Morpholines; D010620:Phenazocine; D039381:RNA Cap-Binding Proteins; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C012134:SK&F 10047