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Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

Hua Su1, Fei Yang2, Rao Fu2

  • 1Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.

Cancer Cell
|March 19, 2021
PubMed

Insights

Pancreatic cancer cells adapt to autophagy inhibition by increasing macropinocytosis for nutrients. Combining autophagy and macropinocytosis inhibitors may offer a potent anti-cancer therapy for pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Cellular Biology
  • Cancer Metabolism

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) relies on autophagy for nutrient recycling.
  • Autophagy-inhibiting drugs have shown limited efficacy as monotherapies for cancer.
  • Understanding alternative nutrient pathways is crucial for effective cancer treatment.

Purpose of the Study:

  • To investigate the adaptive mechanisms of PDAC cells upon autophagy blockade.
  • To identify alternative nutrient acquisition pathways utilized by cancer cells.
  • To explore the therapeutic potential of targeting these adaptive pathways.

Main Methods:

  • Utilized established PDAC cell models and in vivo tumor models.
  • Investigated the role of autophagy, macropinocytosis, and the NRF2 pathway.
  • Assessed the impact of inhibiting macropinocytosis in autophagy-compromised tumors.

Main Results:

  • Autophagy blockade in PDAC triggers upregulation of macropinocytosis (MP) for nutrient uptake.
  • The switch to MP is regulated by the p62/SQSTM1-NRF2 signaling axis.
  • Inhibition of MP in autophagy-impaired PDAC tumors led to significant metabolic decline and tumor regression.

Conclusions:

  • PDAC cells adapt to autophagy inhibition by activating macropinocytosis.
  • The p62/SQSTM1-NRF2 pathway mediates this adaptive switch.
  • Combined inhibition of autophagy and macropinocytosis presents a promising therapeutic strategy for PDAC.
Keywords:
NRF2RAS-driven cancerautophagymacropinocytosisp62/SQSTM1

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