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

Kon,Asami; Yuan,Bo; Hanazawa,Tomoyuki; Kikuchi,Hidetomo; Sato,Mari; Furutani,Ryota; Takagi,Norio; Toyoda,Hiroo

doi:10.3892/or.2013.2657

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

Authors:
- Asami Kon
- Bo Yuan
- Tomoyuki Hanazawa
- Hidetomo Kikuchi
- Mari Sato
- Ryota Furutani
- Norio Takagi
- Hiroo Toyoda
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Affiliations: Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Published online on: August 5, 2013 https://doi.org/10.3892/or.2013.2657
Pages: 1965-1970

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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.

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1	Conneely OM, Mulac-Jericevic B, DeMayo F, Lydon JP and O’Malley BW: Reproductive functions of progesterone receptors. Recent Prog Horm Res. 57:339–355. 2002. View Article : Google Scholar : PubMed/NCBI
2	Hughes GC: Progesterone and autoimmune disease. Autoimmun Rev. 11:A502–A514. 2012. View Article : Google Scholar : PubMed/NCBI
3	Matsuzaki J, Tsuji T, Imazeki I, Ikeda H and Nishimura T: Immunosteroid as a regulator for Th1/Th2 balance: its possible role in autoimmune diseases. Autoimmunity. 38:369–375. 2005. View Article : Google Scholar : PubMed/NCBI
4	Ahmad N and Kumar R: Steroid hormone receptors in cancer development: a target for cancer therapeutics. Cancer Lett. 300:1–9. 2011. View Article : Google Scholar : PubMed/NCBI
5	Hellberg D: Sex steroids and cervical cancer. Anticancer Res. 32:3045–3054. 2012.PubMed/NCBI
6	Horita K, Inase N, Miyake S, Formby B, Toyoda H and Yoshizawa Y: Progesterone induces apoptosis in malignant mesothelioma cells. Anticancer Res. 21:3871–3874. 2001.PubMed/NCBI
7	Lanari C, Wargon V, Rojas P and Molinolo AA: Antiprogestins in breast cancer treatment: are we ready? Endocr Relat Cancer. 19:R35–R50. 2012. View Article : Google Scholar : PubMed/NCBI
8	Bertelsen EL, Endresen PC, Orbo A and Sager G: Non-genomic cell growth inhibition by progesterone. cell cycle retardation and induction of cell death. Anticancer Res. 24:3749–3755. 2004.PubMed/NCBI
9	Falkenstein E, Tillmann HC, Christ M, Feuring M and Wehling M: Multiple actions of steroid hormones - a focus on rapid, nongenomic effects. Pharmacol Rev. 52:513–556. 2000.PubMed/NCBI
10	Zhu Y, Hanna RN, Schaaf MJ, Spaink HP and Thomas P: Candidates for membrane progestin receptors - past approaches and future challenges. Comp Biochem Physiol C Toxicol Pharmacol. 148:381–389. 2008. View Article : Google Scholar : PubMed/NCBI
11	Hammes SR and Levin ER: Minireview: recent advances in extranuclear steroid receptor actions. Endocrinology. 152:4489–4495. 2011. View Article : Google Scholar : PubMed/NCBI
12	Ndiaye K, Poole DH, Walusimbi S, Cannon MJ, Toyokawa K, Maalouf SW, Dong J, Thomas P and Pate JL: Progesterone effects on lymphocytes may be mediated by membrane progesterone receptors. J Reprod Immunol. 95:15–26. 2012. View Article : Google Scholar : PubMed/NCBI
13	Dressing GE, Goldberg JE, Charles NJ, Schwertfeger KL and Lange CA: Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications. Steroids. 76:11–17. 2011. View Article : Google Scholar : PubMed/NCBI
14	Thomas P: Characteristics of membrane progestin receptor alpha (mPRα) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol. 29:292–312. 2008.
15	Gamberucci A, Giunti R and Benedetti A: Progesterone inhibits capacitative Ca²⁺ entry in Jurkat T lymphocytes by a membrane delimited mechanism, independently of plasma membrane depolarization. Cell Calcium. 36:175–180. 2004.PubMed/NCBI
16	Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S, Dong J, Thomas P and Giudice LC: Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol. 196:67–77. 2008. View Article : Google Scholar : PubMed/NCBI
17	Juo P, Kuo CJ, Yuan J and Blenis J: Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol. 8:1001–1008. 1998. View Article : Google Scholar : PubMed/NCBI
18	Juo P, Woo MS, Kuo CJ, Signorelli P, Biemann HP, Hannun YA and Blenis J: FADD is required for multiple signaling events downstream of the receptor Fas. Cell Growth Differ. 10:797–804. 1999.PubMed/NCBI
19	Thomas P, Tubbs C, Detweiler C, Das S, Ford L and Breckenridge-Miller D: Binding characteristics, hormonal regulation and identity of the sperm membrane progestin receptor in Atlantic croaker. Steroids. 70:427–433. 2005. View Article : Google Scholar : PubMed/NCBI
20	Zhu Y, Rice CD, Pang Y, Pace M and Thomas P: Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci USA. 100:2231–2236. 2003. View Article : Google Scholar : PubMed/NCBI
21	Imai M, Kikuchi H, Denda T, Ohyama K, Hirobe C and Toyoda H: Cytotoxic effects of flavonoids against a human colon cancer derived cell line, COLO 201: a potential natural anti-cancer substance. Cancer Lett. 276:74–80. 2009. View Article : Google Scholar : PubMed/NCBI
22	Darzynkiewicz Z, Bruno S, Del Bino G, Gorczyca W, Hotz MA, Lassota P and Traganos F: Features of apoptotic cells measured by flow cytometry. Cytometry. 13:795–808. 1992. View Article : Google Scholar : PubMed/NCBI
23	Yoshino Y, Yuan B, Kaise T, Takeichi M, Tanaka S, Hirano T, Kroetz DL and Toyoda H: Contribution of aquaporin 9 and multidrug resistance-associated protein 2 to differential sensitivity to arsenite between primary cultured chorion and amnion cells prepared from human fetal membranes. Toxicol Appl Pharmacol. 257:198–208. 2011. View Article : Google Scholar
24	Yuan B, Ohyama K, Bessho T and Toyoda H: Contribution of inducible nitric oxide synthase and cyclooxygenase-2 to apoptosis induction in smooth chorion trophoblast cells of human fetal membrane tissues. Biochem Biophys Res Commun. 341:822–827. 2006. View Article : Google Scholar : PubMed/NCBI
25	Johnson LV, Walsh ML and Chen LB: Localization of mitochondria in living cells with rhodamine 123. Proc Natl Acad Sci USA. 77:990–994. 1980. View Article : Google Scholar : PubMed/NCBI
26	Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X and Choi AM: Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 9:49–89. 2007. View Article : Google Scholar : PubMed/NCBI
27	Yuan B, Yoshino Y, Kaise T and Toyoda H: Application of arsenic trioxide therapy for patients with leukaemia. Biological Chemistry of As, Sb and Bi. Sun HZ: John Wiley & Sons, Ltd; New York: pp. 263–292. 2011
28	Earnshaw WC, Martins LM and Kaufmann SH: Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 68:383–424. 1999. View Article : Google Scholar : PubMed/NCBI
29	Kantari C and Walczak H: Caspase-8 and bid: caught in the act between death receptors and mitochondria. Biochim Biophys Acta. 1813:558–563. 2011. View Article : Google Scholar : PubMed/NCBI
30	Viswanath V, Wu Y, Boonplueang R, Chen S, Stevenson FF, Yantiri F, Yang L, Beal MF and Andersen JK: Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease. J Neurosci. 21:9519–9528. 2001.PubMed/NCBI
31	Bamberger CM, Else T, Bamberger AM, Beil FU and Schulte HM: Dissociative glucocorticoid activity of medroxyprogesterone acetate in normal human lymphocytes. J Clin Endocrinol Metab. 84:4055–4061. 1999.PubMed/NCBI
32	Xie M, Zhu X, Liu Z, Shrubsole M, Varma V, Mayer IA, Dai Q, Chen Q and You S: Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study. PloS One. 7:e351982012. View Article : Google Scholar : PubMed/NCBI
33	Karteris E, Zervou S, Pang Y, Dong J, Hillhouse EW, Randeva HS and Thomas P: Progesterone signaling in human myometrium through two novel membrane G protein-coupled receptors: potential role in functional progesterone withdrawal at term. Mol Endocrinol. 20:1519–1534. 2006. View Article : Google Scholar