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Review
. 2021 May;17(5):1077-1095.
doi: 10.1080/15548627.2020.1752548. Epub 2020 May 13.

Autophagy in the physiological endometrium and cancer

Laura Devis-Jauregui  1 , Núria Eritja  2 , Meredith Leigh Davis  3 , Xavier Matias-Guiu  1   2   4 , David Llobet-Navàs  1
Affiliations
Review

Autophagy in the physiological endometrium and cancer

Laura Devis-Jauregui et al. Autophagy. 2021 May.

Abstract

Autophagy is a highly conserved catabolic process and a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. An increasing body of evidence has unveiled autophagy as an indispensable biological function that helps to maintain normal tissue homeostasis and metabolic fitness that can also lead to severe consequences for the normal cellular functioning when altered. Recent accumulating data point to autophagy as a key player in a wide variety of physiological and pathophysiological conditions in the human endometrium, one of the most proficient self-regenerating tissues in the human body and an instrumental player in placental species reproductive function. The current review highlights the most recent findings regarding the process of autophagy in the normal and cancerous endometrial tissue. Current research efforts aiming to therapeutically exploit autophagy and the methodological approaches used are discussed.Abbreviations: 3-MA: 3-methyladenine; ACACA (acetyl-CoA carboxylase alpha); AICAR: 5-aminoimidazole-4-carboximide riboside; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG3: autophagy related 3; ATG4C: autophagy related 4C cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; Baf A1: bafilomycin A1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CACNA1D: calcium voltage-gated channel subunit alpha1 D; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CASP9: caspase 9; CD44: CD44 molecule (Indian blood group); CDH1: cadherin 1; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTNNB1: catenin beta 1; DDIT3: DNA damage inducible transcript 3; EC: endometrial cancer; EGFR: epidermal growth factor receptor; EH: endometrial hyperplasia; EIF4E: eukaryotic translation initiation factor 4E; EPHB2/ERK: EPH receptor B2; ER: endoplasmic reticulum; ERBB2: er-b2 receptor tyrosine kinase 2; ERVW-1: endogenous retrovirus group W member 1, envelope; ESR1: estrogen receptor 1; FSH: follicle-stimulating hormone; GCG/GLP1: glucagon; GFP: green fluorescent protein; GIP: gastric inhibitory polypeptide; GLP1R: glucagon-like peptide-1 receptor; GLS: glutaminase; H2AX: H2A.X variant histone; HIF1A: hypoxia inducible factor 1 alpha; HMGB1: high mobility group box 1; HOTAIR: HOX transcript antisense RNA; HSPA5: heat shock protein family A (HSP70) member 5; HSPA8: heat shock protein family A (HSP70) member 8; IGF1: insulin like growth factor 1; IL27: interleukin 27; INS: insulin; ISL: isoliquiritigenin; KRAS: KRAS proto-oncogene, GTPase; LAMP2: lysosomal-associated membrane protein 2; lncRNA: long-non-coding RNA; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK8: mitogen-activated protein kinase 8; MAPK9: mitogen-activated protein kinase 9; MPA: medroxyprogesterone acetate; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYCBP: MYC-binding protein; NFE2L2: nuclear factor, erythroid 2 like 2; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; NK: natural killer; NR5A1: nuclear receptor subfamily 5 group A member 1; PARP1: poly(ADP-ribose) polymerase 1; PAX2: paired box 2; PDK1: pyruvate dehydrogenase kinase 1; PDX: patient-derived xenograft; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3R1: phosphoinositide-3-kinase regulatory subunit 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPD: protopanaxadiol; PRKCD: protein kinase C delta; PROM1/CD133: prominin 1; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; RSV: resveratrol; SGK1: serum/glucocorticoid regulated kinase 1; SGK3: serum/glucocorticoid regulated kinase family member 3; SIRT: sirtuin; SLS: stone-like structures; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1: sequestosome 1; TALEN: transcription activator-like effector nuclease; TGFBR2: transforming growth factor beta receptor 2; TP53: tumor protein p53; TRIB3: tribbles pseudokinase 3; ULK1: unc-51 like autophagy activating kinase 1; ULK4: unc-51 like kinase 4; VEGFA: vascular endothelial growth factor A; WIPI2: WD repeat domain, phosphoinositide interacting 2; XBP1: X-box binding protein 1; ZFYVE1: zinc finger FYVE domain containing 1.

Keywords: Autophagy; endometrial cancer; endometrial hyperplasia; endometrium; menstrual cycle; obesity; reproduction.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
Schematic representation of the autophagy process. Autophagy is a multi-stage process that comprises several steps: initiation, expansion, closure, and fusion with the endolysosomal system. The process initiates with the progressive sequestration of a portion of the cytoplasm that is enclosed within a double-membrane (a phagophore) to finally form an autophagosome. The initiation involves the transmission of the autophagy signal, which is triggered by multiple conditions, such as nutrient starvation, and canalized through specific cell sensors such as AMP-activated protein kinase (AMPK), HIF1A (hypoxia-inducible factor alpha) and mechanistic target of rapamycin kinase complex 1 (MTORC1) to the membrane of origin at which the nucleation takes place. As a consequence, there is a recruitment of the key initiation complexes. The ULK1 (unc-51 like autophagy activating kinase 1) complex plays a central role in the initiation stage, and it is the target of these signaling pathways and, when activated, triggers the nucleation of the phagophore by phosphorylating components of the class III phosphatidylinositol 3-kinase (PtdIns3k) complex I. Then, WIPI2 (WD repeat domain, phosphoinositide interacting 2), and ZFYVE1 (zinc finger FYVE domain containing 1) are recruited to the omegasome. WIPI2 binds and is activated by phosphatidylinositol 3-phosphate (PtdIns3P). Once activated, WIPI2 recruits at phagophore assembly sites the ATG12–ATG5-ATG16L1 complex that enhances the ATG3-mediated conjugation of LC3 (microtubule-associated protein light chain 3) to phosphatidylethanolamine. LC3-I is converted into its lipidated form, LC3-II. Membrane material for the nucleation of the phagophore and the elongation of the autophagic membrane arises from the ER, mitochondria, recycling endosomes, Golgi apparatus, and plasma membrane from which ATG9-containing vesicles provide portions of lipid bilayers. Finally, the expansion continues until the complete formation and closure of the autophagosome. The outer membrane of the autophagosome subsequently fuses with the lysosome, giving rise to the autolysosome. After lysosomal digestion, the sequestered cytoplasmic material is degraded into amino acids and macromolecules, transported across the lysosomal membrane to the cytosol, and finally recycled for anabolic processes
Figure 2.
Figure 2.
Illustration of endometrial layers and tissue components dynamic changes during the course of the different phases of the menstrual cycle. The endometrium, composed of a single layer of columnar epithelial cells plus stroma, can be subdivided into two layers: the functional, which faces the uterine cavity, and the basal layer in direct contact with the myometrium. Both layers undergo structural changes during the menstrual cycle. Menstruation constitutes the first phase of the menstrual cycle, and it is characterized by the complete desquamation of the functional layer of the endometrium and bleeding (menses). This stage precedes the proliferative phase, characterized by the increase in the synthesis and secretion of estrogens as the ovarian follicles mature (ovarian follicular phase). The estrogens will promote the regeneration of the functional layer from the basal layer of the endometrium. By day 14, a peak in LH secretion triggers a decrease in estrogen production, ovulation, and the formation of the corpus luteum (luteal ovarian phase), which represents the primary source of progesterone. Progesterone will prepare the endometrium for future implantation by fostering global endometrial thickening characterized by increased spiral artery length and coiling, uterine secretions, and reduced smooth muscle cell contractility. In the absence of pregnancy, the demise of the corpus luteum will cause a dramatic drop in the progesterone and estrogen levels, and the initiation of the menstruation starts again
Figure 3.
Figure 3.
Illustration of the principal autophagy-related function into the human endometrium. Autophagy has a crucial role in both normal and pathological endometrium and has been linked to endometrial cancer development
See this image and copyright information in PMC

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Grants and funding

This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects PI18/00795, CP17/00063 and MS17/00063 (Co-funded by European Regional Development Fund. ERDF, a way to build Europe) and by the AECC Scientific Foundation (FC_AECC #LABAE19004LLOB). We also want to thank CERCA Programme/Generalitat de Catalunya for institutional support. DLN and NE are recipients of a Miguel Servet scheme; Ministerio de Ciencia, Innovación y Universidades, Gobierno de España (ES).
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