Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT ERK1/2 and mTOR

Capsule:
Dienogest promotes the induction of autophagy in endometriotic cells by suppressing protein kinase B and extracellular-signal-regulated kinase 1/2 activity, which results in mTOR inhibition, ultimately leading to increased apoptosis.

Authors:
JongYeob Choi, Ph.D., MinWha Jo, M.S., EunYoung Lee, M.S., Dong-Yun Lee, M.D., Ph.D., DooSeok Choi, M.D., Ph.D.

Volume 104, Issue 3, Pages 655-664

Abstract:

Objective:
To elucidate the therapeutic mechanisms of progestin and the effects of progesterone and progestin (dienogest) on autophagy induction and regulation in endometriotic cells, specifically the effects of progesterone and dienogest on the phosphoinositide-3/protein kinase B (PI3K-AKT) and mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)/extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways, which activate mammalian target of rapamycin (mTOR), a major negative regulator of autophagy.

Design:
In vitro study using human endometriotic cyst stromal cells (ECSCs).

Setting:
University medical center.

Patient(s):
Fifteen patients with ovarian endometrioma.

Intervention(s):
ECSCs treated with progesterone or dienogest.

Main Outcome Measure(s):
Autophagy as measured by the expression of the microtubule-associated protein light chain 3-II (LC3-II) and autophagosome formation, and levels of AKT, ERK1/2, and mTOR activity to quantify the phosphorylation of AKT, ERK1/2, and S6K (the downstream target of mTOR).

Result(s):
Progesterone treatment had not statistically significant effect on LC3-II expression, autophagosome formation, or phosphorylation of AKT, ERK1/2, or S6K in estrogen-treated ECSCs. However, dienogest treatment up-regulated LC3-II expression and stimulated autophagosome formation. These effects were accompanied by decreased activation of AKT, ERK1/2, and S6K. Furthermore, incubation of ECSCs with AKT and ERK1/2 inhibitors, which mimicked dienogest-mediated inhibition of AKT and ERK1/2 activity, suppressed S6K activity, followed by an increase in LC3-II expression. In addition, cotreatment with dienogest and 3-methyladenine (autophagy inhibitor) decreased the levels of apoptosis of ECSCs compared with the single treatment with dienogest.

Conclusion(s):
Our results suggest that dienogest treatment of endometriotic cells suppresses AKT and ERK1/2 activity, thereby in turn inhibiting mTOR, inducing autophagy, and promoting apoptosis.

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