How does estrogen work on autophagy?

Figures & data

Table 1. The regulation of E2 on autophagy.

Ligand	Action	Disease	Cell Line or Animal	Tissue	Dose	Effector proteins	Autophagy morphology	Ref
E2	Induce	Breast cancer	MCF-7	breast	10 nM	MAP1LC3-II/MAP1LC3-I, SQSTM1, BCL2, ESR1↓	autophagosome	[8]
		Hypoxia-induced pulmonary hypertension	PAEC	lung	1, 10 nM	MAP1LC3-II, ER-independent	NA	[9]
			Male Sprague-Dawley rats		75 µg/kg/day	MAP1LC3-II, MAP1LC3-I, IFI27, MAPK1↓	NA	[10]
		Nephrotoxicity	mProx24	proximal renal tubule	0.2 mg/kg/day	MAP1LC3-II/MAP1LC3-I, SQSTM1, SOCS3, STAT3↓, MAPK1	autophagosome	[11]
		Osteoporosis	MC3T3-E1	bone	10 nM	MAP1LC3-II/MAP1LC3-I, BCL2, BECN1, AKT1, ULK1	NA	[12]
		Ovarian cancer	Skov-3, Ovcar-3(HTB-161), A2780 (ESR1^−), A2780CP (ESR1^−)	ovary	10 μM	MAP1LC3B-II, MAP1LC3B-I↓, AKT1↓BECN1↓, GAPDH↓	acidic vesicular organelles	[13]
		Parkinson disease	/	CNS	1 mg/kg/day	MAP1LC3-II, MAPK1	autolysosomes/ autophagosomes	[14]
		Renal cell carcinoma	RCC cell lines	kidney	7, 28 µM	MAP1LC3B-II, MAP1LC3B-I↓, SQSTM1	autophagosome	[15]
		Testicular germ cell tumors	TCAM2	testis	1, 10, 100 nM	BECN1, AMBRA1, PIK3C3, UVRAG, PIK3CA-III, ESR2↓, AKT1↓	autophagic vesicles	[16]
	restrict (prevent induced autophagy)	Heart disease	H9c2 cells	heart	10 nM	MAP1LC3-II↓, MAP1LC3-I, ESR2, AKT1, BNIP3	NA	[17]
		Myocardial injury	cardiomyocytes	heart	10 nM	MAP1LC3-II/MAP1LC3-I, ATG5↓, BECN1↓	NA	[18]
		Spinal cord injury	PC12	adrenal medulla	20 nM	MAP1LC3-II↓, MAP1LC3-I, SQSTM1, BECN1↓, ATG5↓, ATG7↓	NA	[19]
		Ovariectomy	/	proximal tibias	10 µg/kg/day	MAP1LC3-II↓, MAP1LC3-I↓, SQSTM1, ATG5↓, BECN1↓	acidic vesicular	[20]

Abbreviations: AKT1/PKB, AKT serine/threonine kinase 1; AMBRA1, autophagy and beclin 1 regulator 1; ATG, autophagy related; BECN1, beclin 1; BNIP3, BCL2 interacting protein 3; CNS, central nervous system; E2, 17β-estradiol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFI27/p27, interferon alpha inducible protein 27; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK1/ERK, mitogen-activated protein kinase 1; PAEC, pulmonary artery endothelial cells; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN2/ADRP, perilipin 2; SOCS3, suppressor of cytokine signaling 3; SQSTM1/p62, sequestosome 1; STAT, signal transducer and activator of transcription; ULK1, unc-51 like autophagy activating kinase 1; UVRAG, UV radiation resistance associated. ↓, genes are upregulated by E2 unless so marked, which indicates that E2 downregulates them.

Table 2. The regulation of autophagy by ESR ligands ^a.

Disease	Tissue	Cell line	Ligand	Type	Dose	Effector proteins	Autophagy morphology	Ref
Breast cancer	breast	MCF-7	Fulv	ER antagonist	1 μM	MAP1LC3-II, MAP1LC3-I, BCL2↓, BECN1, MAPK/ERK, AKT1↓	autophagosomes	[21,22]
		T47D, MCF-7, BT-474, tam	4-OH TAM	ER antagonist	0.5, 1, 5 μM	MAP1LC3-II, NO, MAPK1, PLIN2, BCL2↓	autophagosomes, lysosomes/autolysosomes increased	[23,24]
		MCF-7, MCF-7 tamR, LCC2, MDA-MB-231	TAM	SERM	1, 3, 5 μM	MAP1LC3-II/MAP1LC3-I, SQSTM1, BECN1, MAPK1/3, BAX-BCL2, ATG12–ATG5	autophagic vacuoles, increases autophagosomes /MDC-labeled vesicles	[21,22,25–28]
		MCF-7	raloxifene	SERM	10 μM	MAP1LC3-II, BECN1, ATG12–ATG5 conjugates	autophagic flux, autophagic vacuoles	[29]
		MCF-7/LCC1, MCF-7/LCC9, MCF-7CL	L17 WAY-20,070	ESR2 agonist	10 nM	MAP1LC3-II/MAP1LC3-I, BCL2↓, ESR1↓	NA	[30]
		MCF-7, (CCD1059sK	genistein	GPER1 agonist	100 μM	MAP1LC3/MAP1LC3B, BAX-BCL2	autophagosome	[31]
		MCF-7, MCF10a, MDA-MB-231	resveratrol	mixed ER agonist/antagonist	100 μM	MAP1LC3-II↓, MAP1LC3-I↓, SQSTM1	prevents rapamycin-induced upregulation of autophagy	[32]
Diabetic cardiac function l	heart	H9c2	resveratrol	mixed ER agonist/antagonist	100 μM	estrogen-regulated genes	induces RICTOR and activates AKT1	[33]
Pituitary tumor	pituitary gland	GH3	resveratrol	mixed ER agonist/antagonist	25, 50 μM	MAP1LC3-II/MAP1LC3-I, BECN1, BCL2↓,	NA	[34]
Glioblastoma	glioblastoma	U87, X1016, JX6	TAM	SERM	9, 12 μM	MAP1LC3-II, MAP1LC3-I, ATG5↓	induces autophagic vacuole formation	[35]
Oral squamous cell carcinoma	mouth	SCC4, SCC9, HSC-3	G15	GPER1 antagonist	0–20 μM	MAP1LC3B-II, MAP1LC3B-I, BCL2↓, AKT1↓, MAPK1↓, GPER1↓	autophagosome	[36]
Osteosarcoma	bone	MG63	2-ME	GPER1 agonist	10 μM	MAP1LC3-II/MAP1LC3-I	NA	[37]
Ovarian cancer	ovary	PEO1, BG-1, SKOV-3R	Fulv	ER antagonist	1 μM	MAP1LC3-II, MAP1LC3-I, IFI27, PARP1, ESR1↓	induces autophagy (not alone)	[38,39]
Toxoplasmosis	breast	MCF-7	TAM	SERM	5, 10 μM	MAP1LC3-II, MAP1LC3-I	NA	[40]

^a Abbreviations: 2-ME, 2-methoxyestradiol; 4-OH TAM, 4-hydroxytamoxifen; BAX, BCL2 associated X, apoptosis regulator; BCL2, BCL2, apoptosis regulator; Fulv, fulvestrant; MTOR, mechanistic target of rapamycin kinase; MDC, monodansylcadaverine; RICTOR, RPTOR independent companion of MTOR complex 2; SERM, selective estrogen receptor modulator; TAM, tamoxifen. ↓, genes are upregulated by ESR ligands unless so marked, which indicates that ESR ligands downregulate them.

Figure 1. Schematic view of ESR distribution in organs.

Figure 2. Action of ESR ligands on autophagy. Dashed lines indicate tissue type-dependent activation or inhibition; dotted lines indicate crosstalk between receptors.

Table 3. Autophagy proteins regulated by E2 via TFs.

Autophagy proteins	TFs	Effect of TFs on Autophagy	Tissue or Cell Line	Ref	Receptor	Effect of E2 on TFs	Tissue or Cell Line	Ref
Regulation of autophagy induction
ULK1	CEBPB	Enhance	Mouse liver	[61]	ESR1	PRKCA enhances CEBPB by MAPK14	HL-60	[62]
						PRKCA and ESR1 are inversely related	Breast cancer	[63]
					GPER1	E2 activates GPER1-cAMP-PRKA-CREB	MCF-7	[144]
						CREB controls CEBPB by TATA box	Rat liver	[65]
	FOXO3	Enhance	Mouse skeletal muscle	[68]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
	TP53	Enhance	Human HCT116 cells	[72]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
	ZKSCAN3	Suppress	Human HeLa cells	[145]	ESR1	ESR1 is inversely related to PRKC	Breast cancer	[63]
						PRKC inactivates ZKSCAN3 by MAPK14	Mouse	[77]
Vesicle nucleation
ATG14	FOXO3	Enhance	Mouse liver	[66]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	Estrogen inactivates FOXO3	MCF-7	[71]
BCL2	NFKB1	Enhance	Rat hippocampal neurons	[78]	ESR1	ESR1 inhibits NFKB1 activity	MCF-7, HeLa, HEK293, HepG2	[82]
					ESR2	ESR2 inhibits NFKB1 activity	HeLa, U937, HCASMC, COV434.	[82]
					GPER1	Activation of GPER1 decreases the transcriptional activities of NFKB1	MDA-MB-231	[83]
	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
					ESR2	(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
	STAT3	Suppress	B cell lymphoma	[84]	ESR1	ESR1 increases STAT3 transactivation	MCF-7	[86]
					GPER1	GPER1 decreases STAT3	MDA-MB-231	[83]
	TP53 (TP63, TP73)	Suppress	Human HCT116 cells	[72,146]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
BECN1	FOXO3	Enhance	Mouse skeletal muscle	[68,147]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
	JUN	Enhance	Human cancer cells CNE2 and Hep3B	[92]	ESR1	E2 induces the MAPK1/3, JUN, and MAPK14-dependent mitochondrial apoptotic pathway	Mouse spermatocyte-derived cell GC-2	[94]
					GPER1		MCF-7	[95]
	NFKB1	Enhance	Human T-cells	[79]	ESR1	ESR1 inhibits NFKB1	MCF-7, HeLa, HEK293, HepG2	[82]
					ESR2	ESR2 inhibits NFKB1	HeLa, U937, HCASMC, COV434.	[82]
					GPER1	GPER1 decreases NFKB1	MDA-MB-231	[83]
PIK3C3	FOXO3	Enhance	Mouse skeletal muscle	[67]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
UVRAG	TP53	Enhance	Human HCT116 cells	[72]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
Vesicle elongation
ATG4	FOXO3	Enhance	Mouse skeletal muscle	[147]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
	TP53	Enhance	Human HCT116 cells	[72]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
ATG7	TP53	Enhance	Human HCT116 cells	[72]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
ATG10	TP53	Enhance	Human HCT116 cells	[72]	ESR1,	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
ATG12	FOXO3	Enhance	Mouse skeletal muscle	[147]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
BNIP3	CEBPB	Enhance	Mouse liver	[61]	ESR1	PRKCA enhances CEBPB by MAPK14	HL-60	[62]
						PRKCA and ESR1 are inversely related	Breast cancer	[63]
					GPER1	E2 activates GPER1-cAMP-PRKA-CREB	MCF-7	[144]
						CREB controls CEBPB by TATA box	Rat liver	[65]
	FOXO3	Enhance	Mouse skeletal and heart muscle	[67,69,147]	ESR1	E2 enhances FOXO3 by ESR1	MCF-7	[70]
					GPER1	Estrogen mediates inactivation of FOXO3 by GPER1	MCF-7	[71]
	NFKB1	Suppress	Human pancreatic cancer cells	[80]	ESR1	ESR1 inhibits NFKB1	MCF-7, HeLa, HEK293, HepG2	[82]
					ESR2	ESR2 inhibits NFKB1	HeLa, U937, HCASMC, COV434.	[82]
					GPER1	GPER1 decreases NFKB1	MDA-MB-231	[83]
	HIF1A	Enhance	Human HEK293 cells	[96]	ESR1	ESR1 directly upregulates HIF1A	MCF-7	[99]
					ESR2	ESR2 inhibits activity of HIF1A	HEK293	[97]
					GPER1	GPER1 upregulates HIF1A	HUVEC	[98]
						GPER1 inhibits HIF1A	MDA-MB-231	[83]
	STAT3	Suppress	Human U87 cells	[85]	ESR1	ESR1 increases STAT3 transactivation	MCF-7	[86]
					GPER1	GPER1 decreases STAT3	MDA-MB-231	[83]
MAP1LC3	CEBPB	Enhance	Mouse liver	[61]	ESR1	PRKCA enhance CEBPB by MAPK14	HL-60	[62]
						PRKCA and ESR1 is inversely related	Breast cancer	[63]
					GPER1	E2 activates GPER1-cAMP-PRKA-CREB	MCF-7	[144]
						CREB controls CEBPB by TATA box	Rat liver	[65]
	FOXO3	Enhance	Mouse skeletal and heart muscle	[67–69]	ESR1	E2 enhances FOXO3	MCF-7	[70]
					GPER1	E2 inactivates FOXO3	MCF-7	[71]
	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
	JUN	Enhance	Human nasopharyngeal carcinoma cells	[93]	ESR1	E2 induces the MAPK1/3, JUN, and MAPK14-dependent mitochondrial apoptotic pathway	Mouse spermatocyte-derived cell GC-2	[94]
					GPER1		MCF-7	[95]
	ZKSCAN3	Suppress	Human HeLa cells	[145]	ESR1	ESR1 is inversely related to PRKC	Breast cancer	[63]
						PRKC inactivates ZKSCAN3 by MAPK14	Mouse	[77]
SQSTM1	CTNNB1/β-catenin	Suppress	Human HT29 cells	[136]	ESR1	There is functional interaction between CTNNB1 and ESR1	MCF-7, HCT116 cells, SW480, Drosophila eye	[148]
	NFKB1	Enhance	Human IMR90 and A549 cells	[81]	ESR1	ESR1 inhibits NFKB1	MCF-7, HeLa, HEK293, HepG2	[82]
					ESR2	ESR2 inhibits NFKB1	HeLa, U937, HCASMC, COV434.	[82]
					GPER1	GPER1 decreases activity of NFKB1	MDA-MB-231	[83]
	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
Retrieval
ATG2	TP53	Enhance	Human HCT116 cells	[72]	ESR1	ESR1 represses TP53-mediated transcription	MCF-7	[73]
					ESR2	ESR2 antagonizes ESR1-TP53-mediated transcriptional regulation	MCF-7	[74]
ATG9	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
WIPI2	TFEB	Enhance	Mouse liver	[87]	ESR1	MTORC1 inhibits TFEB	HeLa	[88,89]
						(p)-MTORC1 expression is mainly related to ER	MCF-7	[91]
	ZKSCAN3	Suppress	Human HeLa cells	[145]	ESR1	ESR1 is inversely related to PRKC	Breast cancer	[63]
						PRKC inactivates ZKSCAN3 by MAPK14	Mouse	[77]

Abbreviations: A549, human lung adenocarcinoma cells; CEBPB, CCAAT enhancer binding protein beta; COV434, Human ovarian granulosa tumor cells; CREBBP, CREB binding protein; FOXO3, forkhead box O3; GC-2, a mouse spermatocyte cell line; GCT, granulosa cell tumors; HCASMC, human coronary artery smooth muscle cells; HCT116, human colon carcinoma cells; HEK293, human embryonic kidney 293 cells; HepG2, a human liver cancer cell line; HIF1A, hypoxia inducible factor 1 subunit alpha; HL-60, human promyelocytic cells; HT29, human colorectal carcinoma cells; HUVEC, human umbilical vein endothelial cells; IMR90, normal human lung fibroblasts; MAPK9/JNK2, mitogen-activated protein kinase 9; MAPK14/p38, mitogen-activated protein kinase 14; MTORC1, mechanistic target of rapamycin kinase complex 1; NFKB1/NF-κB, nuclear factor kappa B subunit 1; PRKC/PKC, protein kinase C; SMCs, human coronary artery smooth muscle cells; STAT3, signal transducer and activator of transcription 3; SW480, a p53 double-mutant cell line; TFEB, transcription factor EB; U87, human primary glioblastoma cells; U937, human macrophagy cells; WIPI2, WD repeat domain, phosphoinositide interacting 2 (a homolog of yeast Atg18); ZKSCAN3, zinc finger with KRAB and SCAN domains 3.

Figure 3. Regulation of E2 on core autophagy proteins via TFs. JUN, subunit of AP-1; TP53, tumor protein p53.

Figure 4. Model of how estrogenic regulation of autophagy affects cell fate. E2 helps maintain moderate autophagy and cellular homeostasis. Both deficient and excessive autophagy are abnormal. Deficient autophagy can lead to unfolded protein response (UPR) stress, which may reestablish homeostasis through the induction of autophagy. However, the UPR can further lead to carcinogenesis. The proliferation of cancer may induce a status of hypoxia and starvation, both of which can induce autophagy. Here, if a new balance is achieved, cells still have a chance to survive, which is bad for the treatment of cancer. Only when excessive autophagy releases enough calcium from the endoplasmic reticulum to the cytoplasm can apoptosis be triggered. Furthermore, activated caspases will cleave BECN1 and turn off autophagy. Autophagy inducers may prevent carcinogenesis when autophagy in non-cancer cells is deficient, or they may promote excessive autophagy in cancer cells and lead to apoptosis. Autophagy inhibitors seem to block the survival of cancer cells during starvation; however, the inhibition of autophagy cannot persist. The persistent stimulation of UPR stress also promotes autophagy.

Figure 5. Association between estrogen and autophagy. E2 balances the expression of core autophagy proteins through diverse transcription factors, miRNAs, and histone modifications via signaling pathways downstream of the receptors. The autophagic proteins controlled by E2 are involved in the entire process of autophagy. Lipids released by autophagy are the major source of cholesterol, the precursor of estrogen biosynthesis. E2 in the blood causes a negative feedback to reduce circulating levels of hormones. E2 activates NOS3 and initiates the synthesis of NO via membrane ESRs. NO induces autophagy by suppressing MTOR expression. In addition, some estrogen-regulated TFs and miRNAs can target ESRs. As the major mechanism for ESR degradation in eukaryotic cells, ESRs dissociate from complexes with HSPs upon binding of E2, are ubiquitinated by ubiquitin ligases (ULs), and are targeted for degradation. The fate of mtESRs and lysosomal ESR1 and GPER1 during autophagy is not yet clear. Ac, acetylation; GF, growth factor; HSPs, heat-shock proteins; HRAS, HRas proto-oncogene, GTPase; Me, methylation; RAF1, Raf-1 proto-oncogene, serine/threonine kinase; RTKs, receptor tyrosine kinases; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; ULs, ubiquitin ligases.

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