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Molecular Cancer Research
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Signal Transduction

A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis

Shweta Joshi, Alok R. Singh, Muamera Zulcic and Donald L. Durden
Shweta Joshi
1UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
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Alok R. Singh
1UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
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Muamera Zulcic
1UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
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Donald L. Durden
1UCSD Department of Pediatrics, Moores Cancer Center, University of California, La Jolla, California.
2Division of Pediatric Hematology-Oncology, UCSD Rady Children's Hospital, San Diego, California.
3SignalRx Pharmaceuticals, San Diego, California.
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  • For correspondence: ddurden@ucsd.edu
DOI: 10.1158/1541-7786.MCR-13-0682 Published October 2014
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Abstract

Tumor growth, progression, and response to the hypoxic tumor microenvironment involve the action of hypoxia-inducible transcription factors, HIF1 and HIF2. HIF is a heterodimeric transcription factor containing an inducible HIFα subunit and a constitutively expressed HIFβ subunit. The signaling pathways operational in macrophages regulating hypoxia-induced HIFα stabilization remain the subject of intense investigation. Here, it was discovered that the PTEN/PI3K/AKT signaling axis controls hypoxia-induced HIF1α (HIF1A) and HIF2α (EPAS1) stability in macrophages. Using genetic mouse models and pan-PI3K as well as isoform-specific inhibitors, inhibition of the PI3K/AKT pathway blocked the accumulation of HIFα protein and its primary transcriptional target VEGF in response to hypoxia. Moreover, blocking the PI3K/AKT signaling axis promoted the hypoxic degradation of HIFα via the 26S proteasome. Mechanistically, a macrophage-dominant PI3K isoform (p110γ) directed tumor growth, angiogenesis, metastasis, and the HIFα/VEGF axis. Moreover, a pan-PI3K inhibitor (SF1126) blocked tumor-induced angiogenesis and inhibited VEGF and other proangiogenic factors secreted by macrophages. These data define a novel molecular mechanism by which PTEN/PI3K/AKT regulates the proteasome-dependent stability of HIFα under hypoxic conditions, a signaling pathway in macrophages that controls tumor-induced angiogenesis and metastasis.

Implications: This study indicates that PI3K inhibitors are excellent candidates for the treatment of cancers where macrophages promote tumor progression. Mol Cancer Res; 12(10); 1520–31. ©2014 AACR.

This article is featured in Highlights of This Issue, p. 1345

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received January 21, 2014.
  • Revision received July 21, 2014.
  • Accepted July 27, 2014.
  • ©2014 American Association for Cancer Research.
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Molecular Cancer Research: 12 (10)
October 2014
Volume 12, Issue 10
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A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis
Shweta Joshi, Alok R. Singh, Muamera Zulcic and Donald L. Durden
Mol Cancer Res October 1 2014 (12) (10) 1520-1531; DOI: 10.1158/1541-7786.MCR-13-0682

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A Macrophage-Dominant PI3K Isoform Controls Hypoxia-Induced HIF1α and HIF2α Stability and Tumor Growth, Angiogenesis, and Metastasis
Shweta Joshi, Alok R. Singh, Muamera Zulcic and Donald L. Durden
Mol Cancer Res October 1 2014 (12) (10) 1520-1531; DOI: 10.1158/1541-7786.MCR-13-0682
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Molecular Cancer Research
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