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Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing

Mihyang Park1,2, Jonghwa Jin1, Da Young An3

  • 1Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea.

Cancer Research
|July 29, 2024
PubMed

Insights

Targeting cancer cell glutamine metabolism activates YAP signaling, increasing extracellular matrix deposition. Combining YAP inhibitors with glutamine metabolism inhibitors effectively suppresses tumor growth and reduces matrix accumulation.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Cancer cells develop resistance to glutamine metabolism inhibitors through various mechanisms.
  • Tumor responses to altered glutamine availability present potential therapeutic targets for combination strategies.

Purpose of the Study:

  • To investigate the mechanisms by which targeting glutamine utilization affects cancer cell signaling and the tumor microenvironment.
  • To identify strategies for enhancing the efficacy of glutamine metabolism inhibitors.

Main Methods:

  • Investigated the impact of glutamine utilization inhibition on Yes-associated protein (YAP) signaling.
  • Assessed the role of YAP activation in extracellular matrix (ECM) deposition.
  • Evaluated the synergistic effects of combined YAP and glutamine utilization inhibition in vivo.
  • Examined the impact of blocking ECM remodeling on therapeutic efficacy.

Main Results:

  • Inhibition of glutamine utilization stimulated YAP signaling by reducing LATS phosphorylation.
  • Activated YAP increased ECM deposition via connective tissue growth factor secretion, promoting fibronectin and collagen production by fibroblasts.
  • Combined inhibition of YAP and glutamine utilization synergistically suppressed tumor growth in vivo with decreased ECM deposition.
  • Blocking ECM remodeling enhanced the tumor-suppressive effects of glutamine utilization inhibitors.

Conclusions:

  • Targeting glutamine utilization activates YAP, leading to increased ECM deposition by fibroblasts.
  • YAP inhibitors and antifibrotic strategies represent promising approaches for combination metabolic therapies in cancer.
  • Reducing ECM levels can enhance the efficacy of glutamine metabolism inhibitors.

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