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Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers

M Sánchez-Aragó1, L Formentini, I Martínez-Reyes

  • 1Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, Madrid, Spain.

Oncogenesis
|April 24, 2013
PubMed

Insights

The ATPase inhibitory factor 1 (IF1) is overexpressed in most human carcinomas, promoting cancer cell survival and proliferation through aerobic glycolysis and reactive oxygen species (ROS) signaling. IF1 shows potential as a predictive marker and therapeutic target in cancer.

Area of Science:

  • Mitochondrial physiology
  • Cancer biology
  • Metabolic reprogramming

Background:

  • Inhibition of mitochondrial H(+)-adenosine triphosphate (ATP) synthase by ATPase inhibitory factor 1 (IF1) in colon cancer cells promotes aerobic glycolysis and reactive oxygen species (ROS) signaling, enhancing proliferation and survival.
  • Understanding IF1's role in various human carcinomas is crucial for identifying new therapeutic targets.

Purpose of the Study:

  • To investigate the expression, biological relevance, regulatory mechanisms, and clinical impact of IF1 in prevalent human carcinomas.
  • To explore IF1's role in metabolic reprogramming and cell survival across different cancer types.

Main Methods:

  • Analysis of IF1 expression in patient cohorts of colon, lung, breast, and ovarian carcinomas using various approaches.
  • Assessment of IF1's impact on aerobic glycolysis and ROS signaling in cancer cell lines.
  • Determination of IF1 protein half-life and investigation of post-transcriptional regulation.
  • Correlation of tumor IF1 expression with clinical outcomes in breast and colon cancer patients.

Main Results:

  • IF1 is highly overexpressed (>90%) in colon, lung, breast, and ovarian carcinomas, with negligible expression in corresponding normal tissues.
  • IF1 overexpression activates aerobic glycolysis and ROS signaling in lung, breast, and ovarian cancer cells, mimicking oligomycin effects.
  • IF1-mediated ROS signaling triggers adaptive responses to prevent cell death.
  • IF1 expression is regulated at post-transcriptional levels, with a short protein half-life (∼100 min) suggesting translational control or protein stabilization.
  • Tumor IF1 expression serves as a predictive marker for clinical outcome in breast and colon cancer patients.

Conclusions:

  • IF1 is a significantly overexpressed protein in major human carcinomas, playing a critical role in promoting cancer cell survival and proliferation.
  • Post-transcriptional regulation and protein stability are key drivers of IF1's function in metabolic reprogramming and survival.
  • IF1 represents a promising therapeutic target and a valuable predictive biomarker for cancer patient outcomes.

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