Blocking autophagy in cancer cells triggered transcription factor NRF2 to induce macropinocytosis.

  • Major Finding: Blocking autophagy in cancer cells triggered transcription factor NRF2 to induce macropinocytosis.

  • Concept: Macropinocytosis provided autophagy-deficient cancer cells with an alternative nutrient source.

  • Impact: This work proposes dual inhibition of autophagy and macropinocytosis to target pancreatic cancer.

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Pancreatic ductal adenocarcinomas (PDAC) often rely on autophagy, the process by which cells degrade and recycle intracellular macromolecules to support metabolic and energetic demands. However, targeting autophagy in combination with chemotherapy has not been sufficient to improve overall survival in patients with pancreatic cancer. Investigating mechanisms that regulate autophagy in PDAC, Su and colleagues found that the protein kinase IKKα (also known as IKK1 or CHUK) promoted autophagosome –lysosome fusion in PDAC cells and that Chuk knockout in KrasG12D-mutant mouse pancreatic epithelial cells or CHUK knockdown in human PDAC cells led to upregulation of macropinocytosis, a nutrient scavenging pathway by which cells acquire nutrients via endocytosis and degradation of extracellular material. Further studies revealed that the increase in macropinocytosis upon genetic or pharmacologic inhibition of autophagy was dependent on transcription factor NRF2 and autophagy receptor p62. Mechanistically, decreased autophagic flux led to an accumulation of p62, which bound and sequestered KEAP1, activating NRF2 and promoting NRF2-mediated macropinocytosis. Accordingly, in human PDAC tumors, the majority of IKKαlo specimens had high p62 and NRF2 expression (n = 25 out of 31). Upon autophagy inhibition in human PDAC cells, NRF2 was recruited to promoter regions of macropinocytosis-related genes, including SDC1, NHE1, CDC42, and PI3KCG, supporting the role of NRF2 as a transcriptional activator of macropinocytosis. In vitro, inhibiting both autophagy and macropinocytosis in PDAC cells synergistically inhibited cell growth, suggesting that macropinocytosis compensated for a deficiency in autophagy by providing an alternative source of amino acids and tricarboxylic acid cycle intermediates. In vivo, dual inhibition of macropinocytosis and autophagy extended survival and decreased tumor volume in multiple genetically engineered and xenograft mouse models of PDAC. Taken together, this work supports a model in which autophagy-deficient cancer cells depend on macropinocytosis and suggests that investigation of dual inhibition of autophagy and macropinocytosis in patients with pancreatic cancer may be warranted.

Su H, Yang F, Fu R, Li X, French R, Mose E, et al. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell 2021 Mar 18 [Epub ahead of print].

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