| Autor: |
Rushika M. Perera, Gina M. DeNicola, Yin Shen, Joseph D. Mancias, Andrew J. Aguirre, Isha H. Jain, Zeynep Cakir, Annelot A.L. Staes, Gilles Rademaker, Brandon R. Desousa, Yang Yang, Connor J. Hennessey, Annan Yang, Miljan Kuljanin, Callum Foakes, Anthony Venida, Nathan P. Ward, Charles Cai, Jingjie Hu, Mirunalini Ravichandran |
| Rok vydání: |
2023 |
| ISSN: |
2159-8290 |
| Popis: |
The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS–MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron–sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS–MAPK inhibition.Significance:Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy–lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS–MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency.See related commentary by Jain and Amaravadi, p. 2023.See related article by Santana-Codina et al., p. 2180.This article is highlighted in the In This Issue feature, p. 2007 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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