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Updated: May 2, 2026
Induction and Testing of Hypoxia in Cell Culture
Published on: August 12, 2011
Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia
Catherine J Kelly1, Kamila Hussien1, Emmanouil Fokas1
1Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
Background:
Inhibitors of the phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathway are currently in clinical trials. In addition to antiproliferative and proapoptotic effects, these agents also diminish tumor hypoxia. Since hypoxia is a major cause of resistance to radiotherapy, we sought to understand how it is regulated by PI3K/mTOR inhibition.
Methods:
Whole cell, mitochondrial, coupled and uncoupled oxygen consumption were measured in cancer cells after inhibition of PI3K (Class I) and mTOR by pharmacological means or by RNAi. Mitochondrial composition was assessed by immunoblotting. Hypoxia was measured in spheroids, in tumor xenografts and predicted with mathematical modeling.
Results:
Inhibition of PI3K and mTOR reduced oxygen consumption by cancer cell lines is predominantly due to reduction of mitochondrial respiration coupled to ATP production. Hypoxia in tumor spheroids was reduced, but returned after removal of the drug. Murine tumors had increased oxygenation even in the absence of average perfusion changes or tumor necrosis.
Conclusions:
Targeting the PI3K/mTOR pathway substantially reduces mitochondrial oxygen consumption thereby reducing tumor hypoxia. These alterations in tumor hypoxia should be considered in the design of clinical trials using PI3K/mTOR inhibitors, particularly in conjunction with radiotherapy.
Insights
Inhibiting phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways reduces cancer cell oxygen consumption, thereby decreasing tumor hypoxia. This finding is crucial for optimizing cancer treatments, especially radiotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathway inhibitors are in clinical trials.
- These inhibitors exhibit antiproliferative and proapoptotic effects and reduce tumor hypoxia.
- Tumor hypoxia is a significant factor contributing to resistance to radiotherapy.
Purpose of the Study:
- To investigate the regulatory mechanisms of PI3K/mTOR inhibition on tumor hypoxia.
- To understand how PI3K/mTOR pathway affects oxygen consumption in cancer cells.
Main Methods:
- Measured oxygen consumption (whole cell, mitochondrial, coupled, uncoupled) in cancer cells following PI3K and mTOR inhibition.
- Assessed mitochondrial composition via immunoblotting.
- Quantified hypoxia in spheroids and tumor xenografts, and employed mathematical modeling for prediction.
Main Results:
- PI3K/mTOR inhibition significantly reduced oxygen consumption, primarily by decreasing mitochondrial respiration linked to ATP production.
- Hypoxia in tumor spheroids decreased upon inhibition but reverted after drug withdrawal.
- Murine tumors showed increased oxygenation without significant changes in perfusion or necrosis.
Conclusions:
- Targeting the PI3K/mTOR pathway effectively lowers mitochondrial oxygen consumption and reduces tumor hypoxia.
- These effects on tumor hypoxia warrant consideration in clinical trial designs involving PI3K/mTOR inhibitors, particularly when combined with radiotherapy.
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