Regulation of O2 consumption by the PI3K and mTOR pathways contributes to tumor hypoxia

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 radiother...

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Vydáno v:	Radiotherapy and oncology Ročník 111; číslo 1; s. 72 - 80
Hlavní autoři:	Kelly, Catherine J., Hussien, Kamila, Fokas, Emmanouil, Kannan, Pavitra, Shipley, Rebecca J., Ashton, Thomas M., Stratford, Michael, Pearson, Natalie, Muschel, Ruth J.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Ireland Elsevier Ireland Ltd 01.04.2014 Elsevier Scientific Publishers
Témata:	Aminopyridines - pharmacology Animals Cell Hypoxia - drug effects Cell Hypoxia - physiology Cell Line, Tumor HCT116 Cells Hematology, Oncology and Palliative Medicine Humans Hypoxia Imidazoles - pharmacology Mice Molecular Radiobiology Morpholines - pharmacology mTOR Neoplasms - enzymology Neoplasms - metabolism Oxidative metabolism Oxygen Consumption - physiology Phosphatidylinositol 3-Kinase - metabolism Phosphoinositide-3 Kinase Inhibitors PI3K Protein Kinase Inhibitors - pharmacology Quinolines - pharmacology Reoxygenation Signal Transduction - drug effects Spheroids, Cellular TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism mTOR Hypoxia PI3K Reoxygenation Oxidative metabolism
ISSN:	0167-8140, 1879-0887, 1879-0887
On-line přístup:	Získat plný text
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Shrnutí:	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. 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. 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. 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0167-8140 1879-0887 1879-0887
DOI:	10.1016/j.radonc.2014.02.007