PPARδ is a regulator of autophagy by its phosphorylation.
Autophagy
/ drug effects
Cell Line, Tumor
Epidermal Growth Factor
/ pharmacology
ErbB Receptors
/ antagonists & inhibitors
Gefitinib
/ pharmacology
HCT116 Cells
Humans
Microtubule-Associated Proteins
/ metabolism
Mutation
PPAR delta
/ genetics
Phosphorylation
/ drug effects
Protein Binding
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Tyrosine
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
04
03
2020
accepted:
07
05
2020
revised:
05
05
2020
pubmed:
23
5
2020
medline:
15
12
2020
entrez:
23
5
2020
Statut:
ppublish
Résumé
In response to nutrient deficiency, autophagy degrades cytoplasmic materials and organelles in lysosomes, which is nutrient recycling, whereas activation of EGFR mediates autophagy suppression in response to growth factors. It is unclear whether PPARδ could be the regulator of autophagy in response to active EGFR. Here we found that EGFR induced PPARδ phosphorylation at tyrosine-108 leading to increased binding of LC3 to PPARδ by its LIR (LC3 interacting region) motif, consequently, inhibited autophagic flux. Conversely, EGFR inhibitor treatment reversed this event. Furthermore, EGFR-mediated PPARδ phosphorylation at tyrosine-108 led to autophagy inhibition and tumor growth. These findings suggest that PPARδ serves as a regulator of autophagy by its phosphorylation.
Identifiants
pubmed: 32439863
doi: 10.1038/s41388-020-1329-x
pii: 10.1038/s41388-020-1329-x
doi:
Substances chimiques
MAP1LC3A protein, human
0
Microtubule-Associated Proteins
0
PPAR delta
0
Protein Kinase Inhibitors
0
Tyrosine
42HK56048U
Epidermal Growth Factor
62229-50-9
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Gefitinib
S65743JHBS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4844-4853Références
Chang SH, Huang SW, Wang ST, Chung KC, Hsieh CW, Kao JK, et al. Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells. J Dermatol Sci. 2017;87:138–48.
pubmed: 28601430
doi: 10.1016/j.jdermsci.2017.04.011
Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16:461–72.
pubmed: 26177004
doi: 10.1038/nrm4024
pmcid: 26177004
Mizushima N, Klionsky DJ. Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr. 2007;27:19–40.
pubmed: 17311494
doi: 10.1146/annurev.nutr.27.061406.093749
Hotchkiss RS, Strasser A, McDunn JE, Swanson PE. Cell death. N. Engl J Med. 2009;361:1570–83.
pubmed: 19828534
pmcid: 3760419
doi: 10.1056/NEJMra0901217
Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control. Nat Rev Cancer. 2005;5:886–97.
pubmed: 16239905
doi: 10.1038/nrc1738
Burton LJ, Rivera M, Hawsawi O, Zou J, Hudson T, Wang G, et al. Muscadine grape skin extract induces an unfolded protein response-mediated autophagy in prostate cancer cells: a TMT-based quantitative proteomic analysis. PLoS ONE. 2016;11:e0164115.
pubmed: 27755556
pmcid: 5068743
doi: 10.1371/journal.pone.0164115
Chang CT, Hseu YC, Thiyagarajan V, Lin KY, Way TD, Korivi M, et al. Chalcone flavokawain B induces autophagic-cell death via reactive oxygen species-mediated signaling pathways in human gastric carcinoma and suppresses tumor growth in nude mice. Arch Toxicol. 2017;91:3341–64.
pubmed: 28374157
doi: 10.1007/s00204-017-1967-0
Chang CH, Lee CY, Lu CC, Tsai FJ, Hsu YM, Tsao JW, et al. Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling. Int J Oncol. 2017;50:873–82.
pubmed: 28197628
doi: 10.3892/ijo.2017.3866
Ba MC, Long H, Cui SZ, Gong YF, Yan ZF, Wang S, et al. Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. Tumour Biol. 2017;39:1010428317711952.
pubmed: 28639902
doi: 10.1177/1010428317711952
Rodolfo C, Rocco M, Cattaneo L, Tartaglia M, Sassi M, Aducci P, et al. Ophiobolin A induces autophagy and activates the mitochondrial pathway of apoptosis in human melanoma cells. PLoS ONE. 2016;11:e0167672.
pubmed: 27936075
pmcid: 5147944
doi: 10.1371/journal.pone.0167672
Nazim UM, Moon JH, Lee YJ, Seol JW, Park SY. PPARgamma activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget. 2017;8:26819–31.
pubmed: 28460464
pmcid: 5432299
doi: 10.18632/oncotarget.15819
You M, Jin J, Liu Q, Xu Q, Shi J, Hou Y. PPARalpha promotes cancer cell Glut1 transcription repression. J Cell Biochem. 2017;118:1556–62.
pubmed: 27918085
doi: 10.1002/jcb.25817
Zhang W, Xu Y, Xu Q, Shi H, Shi J, Hou Y. PPARdelta promotes tumor progression via activation of Glut1 and SLC1-A5 transcription. Carcinogenesis. 2017;38:748–55.
pubmed: 28419191
doi: 10.1093/carcin/bgx035
Khozoie C, Borland MG, Zhu B, Baek S, John S, Hager GL, et al. Analysis of the peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) cistrome reveals novel co-regulatory role of ATF4. BMC Genomics. 2012;13:665.
pubmed: 23176727
pmcid: 3556323
doi: 10.1186/1471-2164-13-665
Venkatachalam G, Kumar AP, Yue LS, Pervaiz S, Clement MV, Sakharkar MK. Computational identification and experimental validation of PPRE motifs in NHE1 and MnSOD genes of human. BMC Genomics. 2009;10(Suppl 3):S5.
pubmed: 19958503
pmcid: 2788392
doi: 10.1186/1471-2164-10-S3-S5
Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer. 2004;4:61–70.
pubmed: 14708026
doi: 10.1038/nrc1254
Hou Y, Moreau F, Chadee K. PPARgamma is an E3 ligase that induces the degradation of NFkappaB/p65. Nat Commun. 2012;3:1300.
pubmed: 23250430
doi: 10.1038/ncomms2270
Hou Y, Gao J, Xu H, Xu Y, Zhang Z, Xu Q, et al. PPARgamma E3 ubiquitin ligase regulates MUC1-C oncoprotein stability. Oncogene. 2014;33:5619–25.
pubmed: 24292674
doi: 10.1038/onc.2013.504
Zhang Z, Xu Y, Xu Q, Hou Y. PPARgamma against tumors by different signaling pathways. Onkologie. 2013;36:598–601.
pubmed: 24107916
doi: 10.1159/000355328
Zhou D, Jin J, Liu Q, Shi J, Hou Y. PPARdelta agonist enhances colitis-associated colorectal cancer. Eur J Pharm. 2019;842:248–54.
doi: 10.1016/j.ejphar.2018.10.050
You M, Gao J, Jin J, Hou Y. PPARalpha enhances cancer cell chemotherapy sensitivity by autophagy induction. J Oncol. 2018;2018:6458537.
pubmed: 30519260
pmcid: 6241347
doi: 10.1155/2018/6458537
Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G, et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell. 2013;154:1269–84.
pubmed: 24034250
pmcid: 3917713
doi: 10.1016/j.cell.2013.08.015
Li X, Lu Y, Pan T, Fan Z. Roles of autophagy in cetuximab-mediated cancer therapy against EGFR. Autophagy. 2010;6:1066–77.
pubmed: 20864811
pmcid: 3039478
doi: 10.4161/auto.6.8.13366
Fung C, Chen X, Grandis JR, Duvvuri U. EGFR tyrosine kinase inhibition induces autophagy in cancer cells. Cancer Biol Ther. 2012;13:1417–24.
pubmed: 22954701
pmcid: 3542232
doi: 10.4161/cbt.22002
Yu JJ, Zhou DD, Cui B, Zhang C, Tan FW, Chang S, et al. Disruption of the EGFR-SQSTM1 interaction by a stapled peptide suppresses lung cancer via activating autophagy and inhibiting EGFR signaling. Cancer Lett. 2020;474:23–35.
pubmed: 31931029
doi: 10.1016/j.canlet.2020.01.004
Han W, Pan H, Chen Y, Sun J, Wang Y, Li J, et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS ONE. 2011;6:e18691.
pubmed: 21655094
pmcid: 3107207
doi: 10.1371/journal.pone.0018691
Birgisdottir AB, Lamark T, Johansen T. The LIR motif—crucial for selective autophagy. J Cell Sci. 2013;126:3237–47.
pubmed: 23908376
Abu El Maaty MA, Strassburger W, Qaiser T, Dabiri Y, Wolfl S. Differences in p53 status significantly influence the cellular response and cell survival to 1,25-dihydroxyvitamin D3-metformin cotreatment in colorectal cancer cells. Mol Carcinog. 2017;56:2486–98.
pubmed: 28618116
doi: 10.1002/mc.22696
Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D, Moreau R. Autophagy in liver diseases. J Hepatol. 2010;53:1123–34.
pubmed: 20810185
doi: 10.1016/j.jhep.2010.07.006
Peng Y, Cao J, Yao XY, Wang JX, Zhong MZ, Gan PP, et al. TUSC3 induces autophagy in human non-small cell lung cancer cells through Wnt/beta-catenin signaling. Oncotarget. 2017;8:52960–74.
pubmed: 28881786
pmcid: 5581085
doi: 10.18632/oncotarget.17674
Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, et al. Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. J Pathol. 2009;217:702–6.
pubmed: 19197948
doi: 10.1002/path.2509
Balakumaran BS, Porrello A, Hsu DS, Glover W, Foye A, Leung JY, et al. MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. Cancer Res. 2009;69:7803–10.
pubmed: 19773438
pmcid: 2756305
doi: 10.1158/0008-5472.CAN-09-0910
Capizzi M, Strappazzon F, Cianfanelli V, Papaleo E, Cecconi F. MIR7-3HG, a MYC-dependent modulator of cell proliferation, inhibits autophagy by a regulatory loop involving AMBRA1. Autophagy. 2017;13:554–66.
pubmed: 28059583
pmcid: 5361610
doi: 10.1080/15548627.2016.1269989
Chung SJ, Nagaraju GP, Nagalingam A, Muniraj N, Kuppusamy P, Walker A, et al. ADIPOQ/adiponectin induces cytotoxic autophagy in breast cancer cells through STK11/LKB1-mediated activation of the AMPK-ULK1 axis. Autophagy. 2017;13:1386–403.
pubmed: 28696138
pmcid: 5584870
doi: 10.1080/15548627.2017.1332565
Lian J, Karnak D, Xu L. The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 2010;6:1201–3.
pubmed: 20930561
pmcid: 3039723
doi: 10.4161/auto.6.8.13549
Bhatelia K, Singh K, Prajapati P, Sripada L, Roy M, Singh R. MITA modulated autophagy flux promotes cell death in breast cancer cells. Cell Signal. 2017;35:73–83.
pubmed: 28366813
doi: 10.1016/j.cellsig.2017.03.024
Park MA, Yacoub A, Sarkar D, Emdad L, Rahmani M, Spiegel S, et al. PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells. Autophagy. 2008;4:513–5.
pubmed: 18299661
pmcid: 2674579
doi: 10.4161/auto.5725
Oh S, Xiaofei E, Ni D, Pirooz SD, Lee JY, Lee D, et al. Downregulation of autophagy by Bcl-2 promotes MCF7 breast cancer cell growth independent of its inhibition of apoptosis. Cell Death Differ. 2011;18:452–64.
pubmed: 20885445
doi: 10.1038/cdd.2010.116
Gou Q, Gong X, Jin J, Shi J, Hou Y. Peroxisome proliferator-activated receptors (PPARs) are potential drug targets for cancer therapy. Oncotarget. 2017;8:60704–9.
pubmed: 28948004
pmcid: 5601172
doi: 10.18632/oncotarget.19610
Yuan S, Jin J, Chen L, Hou Y, Wang H. Naoxintong/PPARgamma signaling inhibits cardiac hypertrophy via activation of autophagy. Evid Based Complement Altern Med. 2017;2017:3801976.
Gao J, Liu Q, Xu Y, Gong X, Zhang R, Zhou C, et al. PPARalpha induces cell apoptosis by destructing Bcl2. Oncotarget. 2015;6:44635–42.
pubmed: 26556865
pmcid: 4792581
doi: 10.18632/oncotarget.5988
He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335–45.
pubmed: 10555149
pmcid: 3779681
doi: 10.1016/S0092-8674(00)81664-5
Peters JM, Morales JL, Gonzalez FJ. Modulation of gastrointestinal inflammation and colorectal tumorigenesis by peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta). Drug Discov Today Dis Mechanisms. 2011;8:e85–e93.
doi: 10.1016/j.ddmec.2011.11.002
You M, Yuan S, Shi J, Hou Y. PPARdelta signaling regulates colorectal cancer. Curr Pharm Des. 2015;21:2956–9.
pubmed: 26004416
doi: 10.2174/1381612821666150514104035
Zuo X, Xu M, Yu J, Wu Y, Moussalli MJ, Manyam GC, et al. Potentiation of colon cancer susceptibility in mice by colonic epithelial PPAR-delta/beta overexpression. J Natl Cancer Inst. 2014;106:dju052.
pubmed: 24681603
pmcid: 3982893
doi: 10.1093/jnci/dju052
Wang D, Fu L, Ning W, Guo L, Sun X, Dey SK, et al. Peroxisome proliferator-activated receptor delta promotes colonic inflammation and tumor growth. Proc Natl Acad Sci USA. 2014;111:7084–9.
pubmed: 24763687
doi: 10.1073/pnas.1324233111
Hollingshead HE, Borland MG, Billin AN, Willson TM, Gonzalez FJ, Peters JM. Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms. Carcinogenesis. 2008;29:169–76.
pubmed: 17893232
doi: 10.1093/carcin/bgm209
Marin HE, Peraza MA, Billin AN, Willson TM, Ward JM, Kennett MJ, et al. Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. Cancer Res. 2006;66:4394–401.
pubmed: 16618765
doi: 10.1158/0008-5472.CAN-05-4277
Zhu B, Ferry CH, Blazanin N, Bility MT, Khozoie C, Kang BH, et al. PPARbeta/delta promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling. Oncogene. 2014;33:5348–59.
pubmed: 24213576
doi: 10.1038/onc.2013.477
Foreman JE, Chang WC, Palkar PS, Zhu B, Borland MG, Williams JL, et al. Functional characterization of peroxisome proliferator-activated receptor-beta/delta expression in colon cancer. Mol Carcinog. 2011;50:884–900.
pubmed: 21400612
pmcid: 3482838
doi: 10.1002/mc.20757
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.
pubmed: 11252954
doi: 10.1038/35052073
Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol, Biol, Phys. 2004;58:903–13.
doi: 10.1016/j.ijrobp.2003.06.002
Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012;318:124–34.
pubmed: 22261334
pmcid: 3304012
doi: 10.1016/j.canlet.2012.01.011
Coelho MA, de Carne Trecesson S, Rana S, Zecchin D, Moore C, Molina-Arcas M, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity. 2017;47:1083–99 e1086.
pubmed: 29246442
pmcid: 5746170
doi: 10.1016/j.immuni.2017.11.016
Xu Y, Jin J, Zhang W, Zhang Z, Gao J, Liu Q, et al. EGFR/MDM2 signaling promotes NF-kappaB activation via PPARgamma degradation. Carcinogenesis. 2016;37:215–22.
pubmed: 26718225
doi: 10.1093/carcin/bgv252
Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 2005;7:575–89.
pubmed: 15950906
doi: 10.1016/j.ccr.2005.05.007
Hou Y, Gao F, Wang Q, Zhao J, Flagg T, Zhang Y, et al. Bcl2 impedes DNA mismatch repair by directly regulating the hMSH2-hMSH6 heterodimeric complex. J Biol Chem. 2007;282:9279–87.
pubmed: 17259174
doi: 10.1074/jbc.M608523200
Hou Y, Mortimer L, Chadee K. Entamoeba histolytica cysteine proteinase 5 binds integrin on colonic cells and stimulates NFkappaB-mediated pro-inflammatory responses. J Biol Chem. 2010;285:35497–504.
pubmed: 20837477
pmcid: 2975174
doi: 10.1074/jbc.M109.066035