Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth

Barbara Wegiel, David Gallo, Eva Csizmadia, Clair Harris, John Belcher, Gregory M. Vercellotti, Nuno Penacho, Pankaj Seth, Vikas Sukhatme, Asif Ahmed, Pier Paolo Pandolfi, Leszek Helczynski, Anders Bjartell, Jenny Liao Persson, Leo E. Otterbein*

*Corresponding author for this work

Research output: Contribution to journalArticle

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 throughmitotic 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. ©2013 AACR.

Original languageEnglish
Pages (from-to)7009-7021
Number of pages13
JournalCancer Research
Volume73
Issue number23
Early online date11 Oct 2013
DOIs
Publication statusPublished - Dec 2013

Bibliographical note

Funding: NIH [HL-071797, HL-076167]; AHA [10SDG2640091]; Julie Henry Fund at the Transplant Center of the BIDMC; British Heart Foundation [PG/06/114]; Medical Research Council [G0601295, G0700288]

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    Wegiel, B., Gallo, D., Csizmadia, E., Harris, C., Belcher, J., Vercellotti, G. M., Penacho, N., Seth, P., Sukhatme, V., Ahmed, A., Pandolfi, P. P., Helczynski, L., Bjartell, A., Persson, J. L., & Otterbein, L. E. (2013). Carbon monoxide expedites metabolic exhaustion to inhibit tumor growth. Cancer Research, 73(23), 7009-7021. https://doi.org/10.1158/0008-5472.CAN-13-1075