Autophagy in endometriosis

Abstract

Endometriosis (EMS) is a common gynecologic disease that causes chronic pelvic pain, dysmenorrhea, and infertility in women. The doctrine of menstruation back flow planting and defects in the immune system are well known and widely accepted. In recent years, increasing studies have been focused on the role of autophagy in EMS, and have shown that autophagy plays a vital role in EMS. Autophagy, which is known as the non-apoptotic form of programmed cell death induced by a large number of intracellular/extracellular stimuli, is the major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles in eukaryotic cells. Autophagy commonly refers to macroautophagy, which is characterized by autophagosomes (double-membrane vesicles). In normal endometrial tissues, autophagy is induced in glandular epithelial and stromal cells throughout the menstrual cycle. However, aberrant autophagy occurs in the eutopic endometrium and ectopic endometriotic foci, which contributes to the pathogenesis of EMS by promoting the hyperplasia of endometriotic tissues and stromal cells, restricting apoptosis, and inducing abnormal immune responses. Consistent with changes in autophagy levels between normal endometria, eutopic and ectopic endometria from patients with EMS, the altered expression of autophagy-related genes (ATGs) is also observed. Currently, many factors are involved in the aberrant autophagy of endometriotic tissues, including female hormones, certain drugs, hypoxia, and oxidative stress. Therefore, studies focusing on autophagy may uncover a new potential treatment for EMS. The aim of this review is to discuss the role of aberrant autophagy in EMS and to explore the potential value of autophagy as a target for EMS therapy.

Keywords: Autophagy; autophagy-related genes; endometrial stromal cells; endometriosis.

Figure 1

Four major stages of autophagosome formation in mammalian cells. I. Initiation. Different stimuli activate AMPK to prevent PI3K from phosphorylating its downstream target Akt, subsequently inhibiting mTOR and reducing the phosphorylation of ATG13. ATG13 interacts with ULK1, FIP 200 and ATG101 to form a ULK1 complex, which facilitates the induction of autophagy. II. Expansion. Activation of the ULK1 complex phosphorylates Beclin1, thereby enhancing the activity of Beclin1-ATG14-VPS34-VPS15-PI3K core complexes. The PI3K complex phosphorylates PI to generate PI3P, which is needed for the recruitment of the PI3P-binding protein ATG18 and its partner ATG2. These proteins are involved in ATG9 recycling. ATG4B cleaves the C-terminal 22 residues of the LC3 precursor (proLC3) to produce LC3-I. Following the interaction of ATG3 (E2-like enzyme) with the ATG16L1 complex (E3-ligase) and ATG7, LC3 is then conjugated to PE to produce LC3-PE (LC3-II). III. Closure. LC3-II specifically localizes to both the inner and outer autophagosomal membranes and remains on mature autophagosomes until they fuse with lysosomes. IV. Fusion. A mature autophagosome directly fuses to a lysosome or first fuses with an endosome before trafficking to the lysosome, forming an autophagolysosome.

Figure 2

Factors involved in regulating the autophagy level in ectopic foci. Female hormones (estrogen and progestogen), several drugs (hydoxychloroquine, rapamycin, mullerian inhibiting substance, GnRH-II antagonist, and bafilomycin A1), hypoxia and oxidative stress are reported to affect the dysregulated autophagy level in EMS via different mechanisms or pathways.

Figure 3

The role of autophagy in the progression of endometriosis. Hormones, hypoxia, oxidative stress, and many other related factors significantly decrease autophagy in the ectopic endometrium, resulting in increased proliferation, invasion and angiogenesis, and decreased apoptosis and NK activity in ectopic foci that ultimately contributes to the occurrence and development of EMS.