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.

Expression and hormonal regulation of membrane progesterone receptors in human astrocytoma cells

“…This report concurs with others studies suggesting that apoptosis inhibition produced by P in teleost granulosa cells and Jurkat cells are also mediated through mPRα [50,51].…”

Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

“…It had also been proposed that the effect of progesterone on T cells is mediated via a membrane-bound PR, 3,20,21 the GR, 13 Glucocorticoid-induced T-cell death has been shown in a number of scenarios, first and foremost in the context of positive and negative thymocyte selection. 23,24 Our results extend these observations and confirm that progesterone induces T-cell death via the GR.…”

“…[14][15][16][17][18][19] However, recent findings suggest that the conventional nuclear progesterone receptor (PR) might not be expressed or might be expressed at a very low level in T cells. It has also been suggested that progesterone could modulate T-cell function via binding to a membrane-bound PR expressed in T cells 3,20,21 or exerts its effects on T cells via binding to the glucocorticoid receptor (GR). It has also been suggested that progesterone could modulate T-cell function via binding to a membrane-bound PR expressed in T cells 3,20,21 or exerts its effects on T cells via binding to the glucocorticoid receptor (GR).…”

“…3,13 These contradictory observations on PR expression need further clarification. It has also been suggested that progesterone could modulate T-cell function via binding to a membrane-bound PR expressed in T cells 3,20,21 or exerts its effects on T cells via binding to the glucocorticoid receptor (GR). The GR is widely expressed in mouse and human leukocytes, 22 belongs to the nuclear receptor superfamily, and regulates gene transcription of inflammation-related genes, ultimately leading to immune suppression.…”

Cytotoxic effects of pyrrolidine dithiocarbamate in small-cell lung cancer cells, alone and in combination with cisplatin

“…After treatment with the IC 50 value of PDTC at 0.3 µM for 24 h, cell cycle analysis was performed using a FACSCanto flow cytometer (Becton-Dickinson, CA, USA) according to methods reported previously with modifications (24,25). A total of 10,000 events were acquired and Diva software and ModFit LT™ Ver.3.0 (Verity Software House, ME, USA) were used to calculate the number of cells at each sub-G 1 , G 0 /G 1 , S and G 2 /M phase fraction.…”