Autophagy in the physiological endometrium and cancer

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


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / physiology*
  • Endometrium / metabolism*
  • Female
  • Humans
  • Hyperplasia / metabolism
  • Neoplasms / metabolism*
  • Placenta / metabolism*
  • Pregnancy


  • Apoptosis Regulatory Proteins

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).