Carbon Monoxide Expedites Metabolic Exhaustion to Inhibit Tumor Growth
- Barbara Wegiel1,
- David Gallo1,
- Eva Csizmadia1,
- Clair Harris1,
- John Belcher5,
- Gregory M. Vercellotti5,
- Nuno Penacho6,
- Pankaj Seth2,
- Vikas Sukhatme2,
- Asif Ahmed4,
- Pier Paolo Pandolfi2,
- Leszek Helczynski3,
- Anders Bjartell3,
- Jenny Liao Persson3, and
- Leo E. Otterbein1
- Authors' Affiliations: 1Department of Surgery, Transplant Institute, 2Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; 3Department of Clinical Sciences, Section of Urological Cancers, 4School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom; 5Department of Laboratory Medicine, University Hospital Malmö, Lund University, Malmö, Sweden; and 6Department of Medicine and Vascular Biology Center, University of Minnesota, Minneapolis, Alfama Inc., Oeiras, Portugal
- Corresponding Authors:
Leo E. Otterbein, Harvard Medical School, Beth Israel Deaconess Medical Center, Transplant Institute, 3 Blackfan Circle, EC/CLS 603, Boston, MA 02215. Phone: 617-735-2851; Fax: 617-735-2844; E-mail: lotterbe{at}bidmc.harvard.edu; and Barbara Wegiel. Phone: 617-735-2846; Email: bwegiel{at}bidmc.harvard.edu
Abstract
One classical feature of cancer cells is their metabolic acquisition of a highly glycolytic phenotype. Carbon monoxide (CO), one of the products of the cytoprotective molecule heme oxygenase-1 (HO-1) in cancer cells, has been implicated in carcinogenesis and therapeutic resistance. However, the functional contributions of CO and HO-1 to these processes are poorly defined. In human prostate cancers, we found that HO-1 was nuclear localized in malignant cells, with low enzymatic activity in moderately differentiated tumors correlating with relatively worse clinical outcomes. Exposure to CO sensitized prostate cancer cells but not normal cells to chemotherapy, with growth arrest and apoptosis induced in vivo in part through mitotic catastrophe. CO targeted mitochondria activity in cancer cells as evidenced by higher oxygen consumption, free radical generation, and mitochondrial collapse. Collectively, our findings indicated that CO transiently induces an anti-Warburg effect by rapidly fueling cancer cell bioenergetics, ultimately resulting in metabolic exhaustion. Cancer Res; 73(23); 1–13. ©2013 AACR.
Footnotes
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Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
- Received April 17, 2013.
- Revision received September 16, 2013.
- Accepted September 18, 2013.
- ©2013 American Association for Cancer Research.
