Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis.
Autophagy
; 19(2): 632-643, 2023 02.
Article
de En
| MEDLINE
| ID: mdl-35786294
ABSTRACT
Cancer-associated fibroblasts (CAFs) are considered one of the most critical stromal cells that interact with pancreatic ductal adenocarcinoma (PDAC) and promote tumor growth, metastasis, and treatment resistance. Previous studies illustrated macroautophagy/autophagy contributes to CAF activation during tumor progression. Here in our study, we found that autophagy deficiency in CAFs impedes CAF activation by inhibiting proline biosynthesis and collagen production. Furthermore, we uncovered that autophagy promotes proline biosynthesis through mitophagy-mediated regulation of NADK2 (NAD kinase 2, mitochondrial), an enzyme responsible for production of mitochondrial NADP(H). Using an orthotopic mouse model of PDAC, we found that inhibiting mitophagy by targeting PRKN (parkin RBR E3 ubiquitin protein ligase) in the stroma reduced tumor weight. Thus, inhibition of CAFs mitophagy might be an attractive strategy for stroma-focused anti-cancer intervention. Abbreviations ACTA2/α-SMA actin alpha 2, smooth muscle, aorta; ACTB/ß-actin actin, beta; ALDH18A1/P5CS aldehyde dehydrogenase 18 family, member A1; ATG3 autophagy related 3; ATG5 autophagy related 5; BNIP3L BCL2/adenovirus E1B interacting protein 3-like; CAFscancer-associated fibroblasts; COL1A1 collagen, type I, alpha 1; DES desmin; ECM extracellular matrix; FABP4 fatty acid binding protein 4, adipocyte; FAP/FAPα fibroblast activation protein; IHC immunohistochemical staining; LAMP1 lysosomal-associated membrane protein 1; NADK2 NAD kinase 2, mitochondrial; PC1 pro-collagen 1; PDAC pancreatic ductal adenocarcinoma; PDGFR platelet derived growth factor receptor; PDPN podoplanin; PRKN parkin RBR E3 ubiquitin protein ligase; PSCs pancreatic stellate cells; VIM vimentin; WT wild-type.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Tumeurs du pancréas
/
Carcinome du canal pancréatique
/
Fibroblastes associés au cancer
Type d'étude:
Prognostic_studies
/
Risk_factors_studies
Limites:
Animals
Langue:
En
Journal:
Autophagy
Année:
2023
Type de document:
Article
Pays d'affiliation:
Chine