Journal
AUTOPHAGY
Volume 19, Issue 2, Pages 632-643Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2022.2093026
Keywords
Autophagy; cancer-associated fibroblasts (CAFs); mitophagy; NADK2; proline biosynthesis
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This study reveals that autophagy deficiency in cancer-associated fibroblasts inhibits their activation by impeding proline biosynthesis and collagen production. Autophagy promotes proline biosynthesis through mitophagy-mediated regulation of NADK2. Inhibiting mitophagy can reduce tumor weight in pancreatic ductal adenocarcinoma.
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.
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