title: PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO).
abstract: Translocator protein (TSPO) is a mitochondrial outer membrane protein of unknown function with high physiological expression in steroidogenic cells. Using TSPO gene-deleted mice, we recently demonstrated that TSPO function is not essential for steroidogenesis. The first link between TSPO and steroidogenesis was established in studies showing modest increases in progesterone production by adrenocortical and Leydig tumor cell lines after treatment with PK11195. To reconcile discrepancies between physiological and pharmacological interpretations of TSPO function, we generated TSPO-knockout MA-10 mouse Leydig tumor cells (MA-10:TspoΔ/Δ) and examined their steroidogenic potential after exposure to either dibutyryl-cAMP or PK11195. Progesterone production in MA-10:TspoΔ/Δ after dibutyryl-cAMP was not different from control MA-10:Tspo+/+ cells, confirming that TSPO function is not essential for steroidogenesis. Interestingly, when treated with increasing concentrations of PK11195, both control MA-10:Tspo+/+ cells and MA-10:TspoΔ/Δ cells responded in a similar dose-dependent manner showing increases in progesterone production. These results show that the pharmacological effect of PK11195 on steroidogenesis is not mediated through TSPO.
authors.affiliation: Department of Animal Science, College of Agriculture and Life Sciences (L.N.T., A.H.Z., V.S.), Cornell University, Ithaca, New York 14853; and Department of Cell Biology and Biochemistry, School of Medicine (D.M.S.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430.
authors.forename: Lan N
authors.initials: LN
authors.lastname: Tu
authors.forename: Amy H
authors.initials: AH
authors.lastname: Zhao
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Stocco
authors.forename: Vimal
authors.initials: V
authors.lastname: Selvaraj
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D017353:Gene Deletion; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D007984:Leydig Cell Tumor / Q000378:metabolism; D051379:Mice; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C463819:Bzrp protein, mouse; D007546:Isoquinolines; D018079:Receptors, GABA; C037850:PK 11195