Suppression of autophagic activation in the mouse uterus by estrogen and progesterone

Abstract

Autophagy is a major cellular catabolic pathway tightly associated with cell survival. The involvement of autophagy in the prolonged survival of blastocysts in the uterus is well established, and it was assumed that ovarian steroid hormones -progesterone (P 4 ) and estrogens -have important roles in the regulation of autophagy. However, information is scarce regarding whether these hormones regulate autophagy in certain hormoneresponsive cellular systems. In this study, we investigated the effects of estrogen and P 4 on autophagic response in the uteri of pregnant mice and in ovariectomized (OVX) mice treated with hormones. During pregnancy, autophagic response is high on days 1 and 2 when the uterus shows an inflammatory response to mating, but it subsides around the time of implantation. Dexamethasone treatment to day 1 pregnant mice reduced autophagy in the uterus. In OVX mouse uteri, estrogen or P 4 reduces autophagic response within 6 h. Glycogen content in OVX uteri was increased by 3-methyladenine treatment, suggesting that autophagy is involved in glycogen breakdown in the hormone-deprived uterus. The classical nuclear receptor antagonists, ICI 182 780 or mifepristone, lead to the recovery of the autophagic response in OVX uteri. The suppression of autophagy by 17b-estradiol is inversely correlated with the accumulation of phospho-mouse target of rapamycin, and rapamycin treatment is moderately effective in the upregulation of autophagic response in OVX mouse uteri. Collectively, this study establishes that the uterine autophagy is induced in hormone-derived environment and is suppressed by hormone treatment. Uterine autophagy may have multiple functions as a responsive mechanism to acute inflammation and as an energy provider by breaking down glycogen under hormone deprivation.

PI3K/AKT/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy

“…The MTT results showed that MPA significantly inhibited the proliferation of parental but not PRCs (Figure 1A). Previous studies21 showed lower expression of PR in PRCs. We also found lower expression of PR in our system (Figure 1B).…”

“…Induction of progestin-resistant EC cell line was described previously 21. Briefly, Ishikawa cells were maintained in Dulbecco’s Modified Eagle’s Medium supplemented with 10% fetal bovine serum, and MPA (Sigma-Aldrich Co., St Louis, MO, USA) was added for 6 months.…”

Sex-specific autophagy modulation in osteoblastic lineage: a critical function to counteract bone loss in female

“…These data suggest that estrogen could negatively regulate autophagy in OST. Autophagy inhibition by estrogen has also been observed in mouse uterus, rat cardiomyocytes and rat motor neurons [32–34]. Conversely, estradiol was shown to increase autophagy mediated by serum deprivation in OB, suggesting that the pro- or anti-autophagy effects of estrogens are cell- and context-dependent [35].…”

Autophagy regulation of physiological and pathological processes in the female reproductive tract

“…Choi et al 15 explored whether hormones regulated autophagy in the mouse uterus and found that high levels of LC3-II, a marker of autophagic activity was detected in the uterus during the first 2 days of pregnancy, coinciding with the highest levels of estrogen (E 2) in the uterus and decreased at day 4 when P4 levels are higher. Incidentally, levels of P62, typically associated with reduced autophagy, also rise at day 4.…”