Regulation and function of autophagy in pancreatic cancer

Figures & data

Figure 1. The process and modulation of autophagy. Autophagy is an intracellular lysosomal-dependent degradation pathway that occurs with the dynamic generation of specific membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). This process is regulated by the ATG family and other proteins (particularly kinases) that form different protein complexes. Abbreviations: AMPK, AMP-activated protein kinase; ATG, autophagy related; BECN1, beclin 1; MTOR, mechanistic target of rapamycin kinase; PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4, phosphoinositide 3-kinase regulatory subunit 4; RB1CC1, RB1 inducible coiled-coil 1; Ub-like, ubiquitin-like; ULK1, unc-51 like autophagy activating kinase 1

Figure 2. Dual role of autophagy regulators in KRAS-driven pancreatic tumorigenesis in mice. Abbreviations: ATG, autophagy related; AGER, advanced glycosylation end-product specific receptor; BNIP3L/NIX, BCL2 interacting protein 3 like; HMGB1, high mobility group box 1; PINK, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; PTEN, phosphatase and tensin homolog; TP53, tumor protein p53

Figure 3. Role of autophagy in the pancreatic cancer microenvironment. The microenvironment of pancreatic cancer has unique characteristics and increased desmoplastic reactions, and is infiltrated by various immune or neural cells. Communication between cells in the microenvironment of pancreatic tumors depends on increased autophagy-dependent release or degradation of mediators (e.g., IL6, ECM, alanine, MHC-I, and exosomes), which ultimately promote cancer cell proliferation, invasion, or immune escape. Abbreviations: ARG1, arginase 1; ECM, extracellular matrix; IL6, interleukin 6; IL10, interleukin 10; KRAS, KRAS proto-oncogene, GTPase; MHC-I, major histocompatibility complex-I; NBR1, NBR1 autophagy cargo receptor; PDAC, pancreatic ductal adenocarcinoma; PDGF, platelet derived growth factor; PSC, pancreatic stellate cell; RAB27A, RAB27A, member RAS oncogene family; STAT3, signal transducer and activator of transcription 3; T cell, T lymphocyte cell; TCA cycle, tricarboxylic acid cycle; TGFB1, transforming growth factor beta 1

Figure 4. Autophagy maintains the metabolism and function of PDAC cells. The autophagy pathway is modulated by different metabolic conditions (e.g., oxidative stress, low glucose, high glucose, and low amino acids) in which cellular components are degraded. During this process, bioenergy intermediates are reused and oxidants are elimated, thereby promoting cell survival. Abbreviations: AGER, advanced glycosylation end-product specific receptor; AMPK, AMP-activated protein kinase; BECN1, beclin 1; GPX1, glutathione peroxidase 1; HMGB1, high mobility group box 1; MTOR, mechanistic target of rapamycin kinase; NFE2L2, nuclear factor, erythroid 2 like 2; NFKB, nuclear factor kappa B; PKM2, M2 splice isoform of PKM (pyruvate kinase M1/2); PINK, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; ROS, reactive oxygen species; SREBF1, sterol regulatory element binding transcription factor 1; STAT3, signal transducer and activator of transcription 3; ULK1, unc-51 like autophagy activating kinase 1

Figure 5. The mechanism of autophagy-dependent ferroptosis in PDAC. Several types of selective autophagy (e.g., ferritinophagy or lipophagy) contribute to ferroptosis in PDAC cells by mediating iron accumulation or lipid peroxidation. Autophagy-dependent ferroptosis plays a dual role in PDAC. On the one hand, small molecule compounds (e.g., erastin or RSL3) or drugs (e.g., rapamycin or zalcitabine) can induce autophagy-dependent ferroptosis for tumor therapy. On the other hand, oxidative stress induces autophagy-dependent ferroptosis in PDAC cells, which leads to the release of mutated KRAS and subsequent macrophage polarization, thereby promoting tumor growth. Abbreviations: AA, arachidonic acid; ACSL4, acyl-CoA synthetase long chain family member 4; ALOX5, arachidonate 5-lipoxygenase; ALOXs, ALOX: arachidonate lipoxygenases; ATF4, activating transcription factor 4; cGAMP, cyclic GMP-AMP; CGAS, cyclic GMP-AMP synthase; CoA, coenzyme A; CTSB, cathepsin B; DUSP1, dual specificity phosphatase 1; FA, fatty acid; Fe²⁺, ferrous iron; Fe³⁺, ferric iron; GPX4, glutathione peroxidase 4; GSH, glutathione; HSPA5, heat shock protein family A (hsp70) member 5; KRAS, KRAS proto-oncogene, GTPase; LPCAT3, lysophosphatidylcholine acyltransferase 3; mtDNA, mitochondrial DNA; MTOR, mechanistic target of rapamycin kinase; NCOA4, nuclear receptor coactivator 4; PE, phosphatidylethanolamine; POLG, DNA polymerase gamma, catalytic subunit; RAB7A, RAB7A, member RAS oncogene family; RAB27A, RAB27A, member RAS oncogene family; STING1/TMEM173, stimulator of interferon response cGAMP interactor 1; system xc⁻, the cystine/glutamate antiporter; TF, transferrin; TFAM, transcription factor A, mitochondrial; TFRC, transferrin receptor

Table 1. Monotherapies that affect autophagy in PDAC

Agent	Model	Autophagy flux	Mechanism	Effect	Ref.
11 k	PANC1 cells; xenografts in mice	↓	N/A	Inhibit autophagy and tumor growth	[182]
Ancistrolikokine E3	PANC1 cells	↓	Inhibit MTOR pathway	Inhibit autophagy and tumor growth	[172]
Aqueous extract of clove	AsPC1 cells	↑	Activate AMPK and ULK1 pathway	Induce autophagy-dependent cell death	[183]
Ascorbate	MiaPACA2, AsPC1, and BxPC3 cells; xenografts in mice	↑	Increase ROS production	Induce autophagy-dependent cell death	[179,184]
BA145	PANC1 cells	↑	Inhibit MTOR pathway	Induce G2/M arrest and cell death	[185]
Cannabinoids	PANC1 cells	N/A	Activate AMPK pathway and inhibit PKM2 function	Inhibit glycolysis and induce autophagy	[186]
CQ	8988 T, 8902, and PANC1 cells; xenografts in mice	↓	Increase ROS production and inhibit autolysosome formation	Inhibit autophagy and tumor growth	[56]
Cucurbitacin I	PANC1 cells	↑	Induce ER stress	Induce autophagy-dependent cell death	[187]
Dandelion root extract	PANC1 and BxPC3 cells	N/A	N/A	Induce autophagy-dependent cell death	[188]
Disulfiram	PANC1 and PDAC6 cells	↑	Activate ERN1-XBP1s pathway	Induce autophagy-mediated apoptosis	[189]
Dp44mT	PANC1, AsPC1, and MiaPACA2 cells	N/A	Decrease HMGCR expression	Induce lysosomal dysfunction	[190]
EAD1	BxPC3 cells	↓	Inhibit autolysosome formation	Inhibit autophagy and tumor growth	[174]
Erastin	MiaPACA2 and CAPAN2 cells	↑	Inhibit SLC7A11 function	Induce autophagy-dependent ferroptotic cell death	[155]
Fisetin	PANC1 cells; xenografts in mice	↓	Increase NUPR1 expression and ER stress	Inhibit autophagy and induce apoptosis	[191]
Gemcitabine	PANC1 and MiaPACA2 cells	↑	Increase VMP1 function	Induce autophagy-dependent apoptosis	[192]
Ginger extract	PANC1, AsPC1, BxPC3, CAPAN2, CFPAC1, Mia PACA2, SW1990, and Panc02 cells; xenografts in mice	↑	Inhibit MTOR and activate MAPK pathway	Induce autophagy-dependent cell death	[193]
IMB-6 G	MiaPACA2 and HUPT3 cells	↑	Increase lysosomal membrane permeabilization	Induce autophagy-mediated apoptosis	[194]
Leflunomide	Patient-derived pancreatic cancer cells; genetically engineered mice	N/A	Induce mitochondrial fusion and mitophagy	Inhibit ATP production and tumor growth	[195]
LZ1	PANC1, BxPC3, AsPC1, CFPAC1, and SW1990 cells; orthotopic mice	↑	Induce NCL (nucleolin) degradation	Induce autophagy-dependent cell death	[196]
Marigold supercritical extract	PANC1 and MiaPACA2 cells	↑	Induce AMPK activation	Induce autophagy-dependent cell death	[197]
Matrine	MiaPACA2 and 8988 T cells; xenografts in mice	↓	Inhibit lysosomal protease function and STAT3 expression	Inhibit autophagy-mediated energy metabolism and tumor growth	[198]
N-(4-(3-aminophenyl) thiazol-2-yl) acetamide 6b	BxPC3 and MiaPACA2 cells	↑	N/A	Induce autophagy-dependent cell death	[199]
Oleandrin	PANC1 cells	↑	Inhibit MTOR and activate MAPK pathway	Induce autophagy-dependent cell death	[178]
Parthenolide	PANC1 and BxPC3 cells	↑	Increase BECN1 and SQSTM1 expression	Induce autophagy-mediated apoptosis	[200]
Penfluridol	PANC1, BxPC3, and AsPC1 cells; xenografts in mice	↑	N/A	Induce autophagy-mediated apoptosis	[201]
Phycocyanin	Capan1, PANC1, and BxPC3 cells; xenografts in mice	↑	Inhibit MTOR pathway and increase BECN1 expression	Induce autophagy-dependent cell death	[202]
Polyoxomolybdates	AsPC1 cells; xenograft in mice	↑	N/A	Induce autophagy-dependent cell death	[203]
Pyrrolidine 20	MiaPACA2 and BxPC3 cells	↑	N/A	Induce autophagy-mediated apoptosis	[204]
Rapamycin	PC2 cells	↑	Increase BECN1 expression	Induce autophagy-dependent cell death	[205]
Rottlerin	Human pancreatic CSCs	↑	Inhibit MTOR pathway and increase BECN1 expression	Induce autophagy-dependent apoptosis	[181]
RSL3	MiaPACA2 cells	↑	Inhibit GPX4 function	Induce autophagy-dependent ferroptotic cell death	[175]
Scalarin	PANC1 and MiaPACA2 cells	N/A	Inhibit AGER expression	Inhibit autophagy and tumor growth	[123]
Sorafenib	MiaPACA2 and CAPAN2 cells	↑	Inhibit SLC7A11 function	Induce autophagy-dependent ferroptotic cell death	[155]
Tocotrienol-rich fraction	PSCs (rat)	↑	Activate BECN1 pathway	Induce mitochondrial dysfunction and cell death	[176,177]
TPEN	PANC1, 8988 T, and BxPC3 cells	↓	Increase ROS production and inhibit lysosomal function	Inhibit autophagy and induce cell death	[173]
Triptolide	S2013 and S2VP10 cells	↑	Inhibit MTOR and activate MAPK pathway	Induce autophagy-dependent cell death	[180]
Ultra pH-sensitive micelles (UPSM)	PANC1 and MiaPACA2 cells; subcutaneous and orthotopic mice	N/A	Inhibit lysosomal catabolism and reduce the generation of amino acids	Inhibit lysosomal catabolism and induce apoptosis	[170]
Zalcitabine	PANC1 and Capan2 cells; xenografts in mice	↑	Activate STING1-mediated DNA-sensing pathway	Induce autophagy-dependent ferroptotic cell death	[162]
Zn-CuO NPs	AsPC1 and MiaPACA2 cells; xenografts in mice	↑	Activate AMPK and increase the level of BECN1 and p-ULK1	Induce autophagy and suppress tumor growth	[206]

Table 2. Combination therapies that affect autophagy in PDAC

Agent	Model	Autophagy flux	Mechanism	Effect	Ref.
Alantolactone and oxaliplatin	PANC1 and MiaPACA2 cells; xenografts in mice	↓	Inhibit lysosomal function	Inhibit autophagy and increase chemosensitivity	[214]
Arsenic trioxide (ATO) and JQ1	PANC1, AsPC1, BxPC3, MiaPACA2, and CFPAC1 cells; xenografts in mice	↓	Inhibit NFE2L2 expression and lysosomal function	Inhibit autophagy and induce apoptosis	[215]
Cannabinoid and gemcitabine	PANC1, PaCa44, PaCa3, CFPAC1, T3M4, and MiaPACA2 cells; xenografts in mice	N/A	Increase ROS production	Induce autophagy-dependent cell death	[216]
Chloroquine-modified HES	AsPC1 and MiaPACA2 cells	↓	Inhibit MAPK pathway	Inhibit autophagy and tumor growth	[217]
Cotylenin A and phenethyl isothiocyanate	MiaPACA2, PANC1, and gemcitabine-resistant PANC1 cells	↑	Increase ROS production	Induce autophagy-dependent ferroptotic cell death	[209]
CP-31,398 and RITA and CQ	PaCa3 and PANC1 cells	↓	Activate AMPK pathway and inhibit autolysosome formation	Induce autophagy-dependent cell death	[212]
Deguelin and doxorubicin	PANC1and MiaPACA2 cells	↓	N/A	Inhibit autophagy and increase chemosensitivity	[211]
DQ661 and gemcitabine	KRPC and PDA4662 cells; xenografts in mice	↓	Inhibit lysosomal function	Inhibit autophagy and tumor growth	[208]
Gossypol and BRD4770	PANC1 cells	↑	Increase BNIP3 expression	Induce autophagy-dependent cell death	[213]
Lumican and gemcitabine	PANC1 and MDAPATC53 cells (human); xenografts in mice	↓	Inhibit AMPK function	Inhibit autophagy and increase chemotherapy sensitization	[207]
LW6 and gemcitabine	6606PDA and MiaPACA2 cells; orthotopic mice	↓	N/A	Inhibit autophagy and induce cell death	[218]
Macrolides and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI)	PANC1 and BxPC3 cells	↓	N/A	Inhibit autophagy and induce cell death	[219]
MPT0L145 and gemcitabine	PANC1 cells	N/A	Inhibit PIK3C3 function	Inhibit autophagy and increase chemosensitivity	[220]
Plectin/MIR9 and doxorubicin	PANC1, CFPAC1, and CAPAN1 cells; xenografts in mice	↓	Inhibit EIF5A2 expression	Inhibit autophagy and increase chemosensitivity	[221]
Plectin/MIR212 nanoparticles and doxorubicin	HPNE, CAPAN1, PANC1, and CFPAC1 cells; xenografts in mice	↑	Inhibit USP9X expression	Induce autophagy-dependent cell death and increase chemosensitivity	[222]
Quercetin and gemcitabine	MiaPACA2, BxPC3, AsPC1, and PANC1cells	↑	Inhibit AGER expression	Induce autophagy-mediated apoptosis	[223]
Rocaglamide A and CQ or bafilomycin A1	MiaPACA2 and PANC1 cells; xenografts in mice	↓	Activate PINK1-PRKN pathway and inhibit autolysosome formation	Inhibit autophagy and induce apoptosis	[224]
Sunitinib and CQ	Panc0203, PANC327, MiaPACA2, Panc02, and KPCP1 cells; orthotopic mice	N/A	Inhibit autolysosome formation and lysosome function	Inhibit autophagy and induce apoptosis	[225]
TPCS2a and CQ	PANC327 cells	↓	Increase ROS production and inhibit autolysosome formation	Inhibit autophagy and increase chemotherapy sensitization	[226]
Troglitazone and IFNB (interferon beta)	BxPC3 cells	↑	Inhibit MTOR pathway	Induce autophagy-dependent cell death	[210]
TR-PTX and HCQ-Lip	BxPC3 and NIH3T3 (rat) cells; xenografts in mice and orthotopic mice	↓	N/A	Inhibit autophagy and crosstalk between tumor cells and fibroblasts	[227]
Ursolic acid and gemcitabine	MiaPACA2 and gemcitabine-resistant MiaPACA2 cells	N/A	Inhibit AGER expression	Induce autophagy-mediated apoptosis and increase chemosensitivity	[228]
VE-822 and CQ	MiaPACA2, PANC327, CFPAC1, and DANG cells; 3D organotypic model; xenografts in mice and orthotopic mice	↓	Inhibit mitochondrial and lysosomal function	Inhibit autophagy and tumor growth	[229]
Verteporfin and gemcitabine	BxPC3, CAPAN2, PANC1, HS766T, and MiaPACA2 cells; xenografts in mice	↓	Inhibit autophagosome formation	Inhibit autophagy and increase chemotherapy sensitization	[230]
Withaferin-A and ER stress aggravators	AsPC1, BxPC3, PANC1, SW1990, and MiaPACA2 cells; xenografts in mice	↓	Inhibit SNARE function	Inhibit autophagy and induce apoptosis	[171]
WP1130 and gemcitabine	PANC1, BxPC3, and MiaPACA2 cells; PDAC xenografts in mice	↓	Inhibit USP9X function	Inhibit autophagy and increase chemosensitivity	[231]
XL765 and CQ	AsPC1, BxPC3, HPAFII, and MiaPACA2 cells; xenografts in mice	↓	Inhibit MTOR pathway and autolysosome formation	Inhibit autophagy and induce apoptosis	[232]
ZST93 and gemcitabine	PANC1 and MiaPACA2 cells; xenografts in mice	↑	N/A	Induce autophagy-dependent cell death and increase chemosensitivity	[233]
Chemical and radiation
Gemcitabine and ionizing radiation	PANC1, AsPC1, and MiaPACA2 cells; xenografts in mice	↑	Increase MAP1LC3 and BECN1 expression	Induce autophagy and suppress tumor growth	[238]
Gemcitabine and noninvasive radiofrequency	PANC1, AsPC1, and MiaPACA2 cells; xenografts in mice and orthotopic mice	↑	N/A	Induce autophagy and increase chemosensitivity	[237]
MG132 and ionizing radiation	MiaPACA2, BxPC3, and PANC1 cells; orthotopic mice	↑	Inhibit TRAF6 expression	Induce autophagy-dependent cell death	[239]
Rapamycin and ionizing radiation	PANC1 cells	↑	Inhibit MTOR pathway	Induce autophagy and increase radiosensitivity	[234]
Seaweed polyphenols and fractionated irradiation	PANC327 and MiaPACA2 cells; xenografts in mice	N/A	Inhibit ATG5, ATG12, and MAP1LC3 expression	Inhibit autophagy and increase radiosensitivity	[240]

Table 3. Published clinical studies on using HCQ to inhibit autophagy in PDAC

Study’s HCQ dose	Phase	Participants	Result	Ref.
400 or 600 mg twice/day	II	20	Effect of autophagy inhibition with HCQ is inconsistent and has negligible therapeutic efficacy.	[246]
200–1200 mg/day	I/II	35	Pre-operative autophagy inhibition with HCQ is safe. Outcomes are encouraging.	[242]
600 mg twice/day	II	112	Additional HCQ treatment could not improve the primary endpoint of overall survival at 12 months.	[244]
600 or 1200 mg twice/day	II	64	Additional HCQ treatment produces greater pathological tumor response and improves the serum biomarker response and immune activity.	[243]

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