2. Academic Validation
  3. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

  • Cancer Cell. 2021 May 10;39(5):678-693.e11. doi: 10.1016/j.ccell.2021.02.016.
Hua Su 1,  Fei Yang 2,  Rao Fu 2,  Xin Li 3,  Randall French 4,  Evangeline Mose 4,  Xiaohong Pu 5,  Brittney Trinh 6,  Avi Kumar 7,  Junlai Liu 6,  Laura Antonucci 6,  Jelena Todoric 8,  Yuan Liu 6,  Yinling Hu 3,  Maria T Diaz-Meco 9,  Jorge Moscat 9,  Christian M Metallo 7,  Andrew M Lowy 4,  Beicheng Sun 10,  Michael Karin 11
Affiliations

Affiliations

  • 1 Laboratory 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.
  • 2 Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.
  • 3 Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA.
  • 4 Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA 92093, USA.
  • 5 Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.
  • 6 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • 7 Institute of Engineering in Medicine, Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA 92093, USA.
  • 8 Laboratory 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 Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria.
  • 9 Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
  • 10 Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China. Electronic address: sunbc@nju.edu.cn.
  • 11 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: karinoffice@health.ucsd.edu.
PMID: 33740421 DOI: 10.1016/j.ccell.2021.02.016
Abstract

Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that Autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that Autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The Autophagy to MP switch, which may be evolutionarily conserved and not Cancer cell restricted, depends on activation of transcription factor NRF2 by the Autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining Autophagy and MP inhibitors in the clinic.

Keywords

NRF2; RAS-driven cancer; autophagy; macropinocytosis; p62/SQSTM1.

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