While cytochrome P450 (CYP)-mediated biosynthesis of arachidonic acid (AA) epoxides promotes tumor growth by driving angiogenesis, cancer cell intrinsic functions of CYPs are less understood. CYP-derived AA epoxides, called epoxyeicosatrienoic acids (EETs), also promote the growth of tumor epithelia. In cancer cells, CYP AA epoxygenase enzymes are associated with STAT3 and mTOR signaling, but also localize in mitochondria, where they promote the electron transport chain (ETC). Recently, the diabetes drug metformin was found to inhibit CYP AA epoxygenase activity, allowing the design of more potent biguanides to target tumor growth. Biguanide inhibition of EET synthesis suppresses STAT3 and mTOR pathways, as well as the ETC. Convergence of biguanide activity and eicosanoid biology in cancer has shown a new pathway to attack cancer metabolism and provides hope for improved treatments that target this vulnerability. Inhibition of EET-mediated cancer metabolism and angiogenesis therefore provides a dual approach for targeted cancer therapeutics.
Bibliographical noteFunding Information:
Support is acknowledged of the Center for Translational Medicine of the UMN. We thank Drs. Michael Pollak, Douglas Yee, Stephen Sligar, Ilia Denisov, Irina Sevrioukova, Thomas Poulos, Ian Blair, John Lipscomb, Bruce Hammock, Jorge Capdevila, John Falck, Emanuel Petricoin, Robert Schumacher, Kalpna Gupta, Elizabeth Amin, and Gunda Georg, and Luis Herrera for very kind and helpful advice in the course of our work. We thank Ashley Mooneyham, Cesar Herrera, Victor Arrieta, Adela Galvan, Fernando Luna, Sebastian Mohar, Alejandra Osorio, Ted Bebi,?and Katherine?Hoversten for contributions to the early phases of this work. We thank Michael Franklin for help with editing of the manuscript. Mitochondrial image credit for Fig. 2 is ChemDraw by Perkin Elmer Informatics. Mitochondrial image credit for Fig. 4 is: Extender_01/stock.adobe. com. We thank Sabrina Porter, Department of Medicine, University of Minnesota for artwork in Fig.?1. We gratefully acknowledge the many authors in the field of CYP monooxygenase biology who have contributed to this field and whose important work was not included in this review due to limitations of space.
Carol Lange, the Dr. Barbara Bowers Fund of the Fairview Foundation, an unrestricted grant from ImmunoMet, Inc. to the University of Minnesota Foundation, and the State of Minnesota and University of Minnesota CTSI through the Translational Product Development Fund (TPDF) to D.A.P. and Dr. Robert Schumacher. We acknowledge a Brainstorm Grant from the Masonic Cancer Center to D.A.P. and Dr. Michael Farrar. We also acknowledge Masonic Cancer Center NIH grant P30-CA077598 (Dr. Douglas Yee, P.I.) for Analytical Biochemistry core support and the National Center for Advancing Translational Sciences of the NIH Award Numbers UL1TR000114 and UL1TR000135 (Dr. Bruce Blazar, P.I.). Instituto Nacional de Cancerologica de México, Patronato del Instituto Nacional de Cancerología, Consejo Nacional de Ciencia y Tecnologia, grant 280148 for visiting student support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding information This study is supported through R01-CA113570, Susan G. Komen Foundation grant KG090861, Randy Shaver Foundation and Community Fund, Minnesota Partnership for Biotechnology and Medical Genomics, University of Minnesota (UMN) Medical School Research Renewal Program to D.A.P. and Dr.
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- Breast cancer
- Cytochrome P450
- Electron transport chain
- Epoxyeicosatrienoic acid