1. Academic Validation
  2. Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis

Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis

  • Autophagy. 2022 Jul 11;1-12. doi: 10.1080/15548627.2022.2093026.
Jingru Bai 1 2 Tong Liu 3 Bo Tu 4 Meng Yuan 1 Zhaoqi Shu 1 Minghe Fan 1 Sihan Huo 1 Yuyao Guo 1 Lina Wang 1 Hua Wang 5 Ying Zhao 1
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Hong Kong, China.
  • 3 Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
  • 4 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 5 Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Third Hospital, Beijing, China.
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/β-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; CAFs:cancer-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.

Keywords

Autophagy; NADK2; cancer-associated fibroblasts (CAFs); mitophagy; proline biosynthesis.

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