Journal
CANCER AND METASTASIS REVIEWS
Volume 37, Issue 2-3, Pages 409-423Publisher
SPRINGER
DOI: 10.1007/s10555-018-9749-6
Keywords
Cytochrome P450; CYP3A4; Epoxyeicosatrienoic acid; Mitochondria; Autophagy; Metformin; Biguanide; Electron transport chain; Hexyl-benzyl-biguanide; Breast cancer
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Funding
- Susan G. Komen Foundation [KG090861]
- Randy Shaver Foundation and Community Fund
- Minnesota Partnership for Biotechnology and Medical Genomics
- University of Minnesota (UMN) Medical School Research Renewal Program
- Fairview Foundation
- ImmunoMet, Inc.
- State of Minnesota
- University of Minnesota CTSI
- Masonic Cancer Center
- Masonic Cancer Center NIH [P30-CA077598]
- National Center for Advancing Translational Sciences of the NIH [UL1TR000114, UL1TR000135]
- Instituto Nacional de Cancerologica de Mexico, Patronato del Instituto Nacional de Cancerologia, Consejo Nacional de Ciencia y Tecnologia [280148]
- [R01-CA113570]
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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.
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