title: Contribution of membrane progesterone receptor α to the induction of progesterone-mediated apoptosis associated with mitochondrial membrane disruption and caspase cascade activation in Jurkat cell lines.
abstract: In the present study, we investigated the effects of progesterone (Pg) on the growth of A3 and its caspase-8-deficient mutant cell line, I9.2, both of which are subclones of a T-cell-derived leukemic Jurkat cell line that lacks the classic cytoplasmic/nuclear Pg receptor. Pg inhibited the cell growth of both cell lines in a dose- and time-dependent manner to a similar extent, regardless of the status of caspase-8 expression. The activation of caspase-9 and -3 was observed in both cell lines following treatment with 50 µM Pg for 24 h. In addition, the activation of caspase-8 was observed in A3 cells. The addition of the pan-caspase inhibitor Boc-D-FMK, significantly suppressed Pg-triggered cytocidal effects in both types of cells. Moreover, exposure to 50 µM Pg for 48 and 72 h resulted in lactate dehydrogenase leakage characteristic of the disruption of cellular membrane integrity. The function of membrane progesterone receptor α coupled directly with the Gi protein was revealed based on the restoration of Pg-triggered loss of mitochondrial membrane potential in the presence of pertussis toxin, an inhibitor specific for Gi protein. These results suggest that growth suppression accompanied with induction of apoptosis by Pg in both Jurkat clone cells was mediated through mitochondrial membrane disruption followed by the activation of the caspase cascade, as a result of the activation of non-genomic effects. The results of the present study provide novel insight into Pg actions toward its use for clinical application in patients with lymphocytic T cell leukemia.
authors.affiliation: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Kon
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hanazawa
authors.forename: Hidetomo
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Mari
authors.initials: M
authors.lastname: Sato
authors.forename: Ryota
authors.initials: R
authors.lastname: Furutani
authors.forename: Norio
authors.initials: N
authors.lastname: Takagi
authors.forename: Hiroo
authors.initials: H
authors.lastname: Toyoda
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001593:Benzyl Compounds / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D019169:Jurkat Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015458:Leukemia, T-Cell; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*
chemical_list: D001593:Benzyl Compounds; C476029:Boc-D-FMK; D061945:Caspase Inhibitors; D006845:Hydrocarbons, Fluorinated; D011980:Receptors, Progesterone; C101118:progesterone receptor A; D011374:Progesterone; D007770:L-Lactate Dehydrogenase; D037342:Pertussis Toxin; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9