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Ectopic ATP synthase blockade suppresses lung adenocarcinoma growth by activating the unfolded protein response

Hsin-Yi Chang1, Hsuan-Cheng Huang, Tsui-Chin Huang

  • 1Institute of Molecular and Cellular Biology, Department of Life Science, Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.

Cancer Research
|July 24, 2012
PubMed

Insights

Ectopic ATP synthase on lung cancer cell membranes drives proliferation. Inhibiting it halts growth by triggering unfolded protein response (UPR) and reactive oxygen species (ROS), offering a potential therapeutic strategy.

Area of Science:

  • Biochemistry
  • Cancer Biology
  • Cellular Biology

Background:

  • Mitochondrial F(1)F(0)-ATP synthase is ectopically expressed on the plasma membrane in cancer.
  • The functional role of this plasma membrane ATP synthase in cancer remains largely undefined.

Purpose of the Study:

  • To investigate the functional role of ectopic plasma membrane ATP synthase in lung adenocarcinoma.
  • To explore the therapeutic potential of inhibiting this enzyme in lung cancer.

Main Methods:

  • Utilized ATP synthase inhibitor citreoviridin to study lung adenocarcinoma cells.
  • Analyzed protein expression profiles and employed siRNA to modulate specific pathways.
  • Assessed cell cycle, proliferation, and anchorage-independent growth.

Main Results:

  • Ectopic ATP synthase and electron transport chain on lung cancer cell plasma membranes support proliferation.
  • Citreoviridin treatment induced cell cycle arrest, inhibited proliferation, and anchorage-independent growth.
  • Inhibition triggered the unfolded protein response (UPR) via PERK, leading to eIF2α phosphorylation and growth arrest, amplified by ROS.

Conclusions:

  • Ectopic plasma membrane ATP synthase has a critical function in lung adenocarcinoma cell proliferation.
  • A positive feedback loop between UPR and ROS converges to block proliferation.
  • Targeting plasma membrane ATP synthase represents a potential therapeutic strategy for lung cancer.

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