CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

Mitra, Ranjana; Guo, Zhijun; Milani, Monica; Mesaros, Clementina; Rodriguez, Mariangellys; Nguyen, Julia; Luo, Xianghua; Clarke, Duncan J.; Lamba, Jatinder K.; Schuetz, Erin G.; Donner, David B.; Narender, P.; Falck, John R.; Capdevila, Jorge H.; Gupta, Kalpna; Blair, Ian A.; Potter, David A.

doi:10.1074/jbc.m110.198515

Cited by 90 publications

(102 citation statements)

References 43 publications

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“…For instance, CYP3A4 promoted the progression of the cell cycle from G 1 to S phase and induced a hypoxic response in Hep3B cells [48] . Other reports indicated that CYP3A4 promotes Stat3-mediated breast cancer cell growth [49] and that its strong expression may be a key feature in an unfavorable prognosis in breast cancer [50] . There are also findings that the pregnane X receptor (PXR), which controls the expression of CYP3A4 [51] , plays an anti-apoptotic role in cancer cells, and this role is independent of the PXR-regulated expression of other cytochrome P450 enzymes [52,53] .…”

Section: Discussionmentioning

confidence: 99%

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

2013

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Aim: To examine whether CYP3A4 overexpression influences the metabolism of anticancer agent imidazoacridinone C-1311 in CHO cells and the responses of the cells to C-1311. Methods: Wild type CHO cells (CHO-WT), CHO cells overexpressing cytochrome P450 reductase (CPR) [CHO-HR] and CHO cells coexpressing CPR and CYP3A4 (CHO-HR-3A4) were used. Metabolic transformation of C-1311 and CYP3A4 activity were measured using RP-HPLC. Flow cytometry analyses were used to examine cell cycle, caspase-3 activity and cell apoptosis. The expression of pH 6.0-dependent β-galactosidase (SA-β-gal) was studied to evaluate accelerated senescence. ROS generation was analyzed with CM-H 2 DCFDA staining. Results: CYP3A4 overexpression did not change the metabolism of C-1311 in CHO cells: the levels of all metabolites of C-1311 increased with the exposure time to a similar extent, and the differences in the peak level of the main metabolite M3 were statistically insignificant among the three CHO cell lines. In CHO-HR-3A4 cells, C-1311 effectively inhibited CYP3A4 activity without affecting CYP3A4 protein level. In the presence of C-1311, CHO-WT cells underwent rather stable G 2 /M arrest, while the two types of transfected cells only transiently accumulated at this phase. C-1311-induced apoptosis and necrosis in the two types of transfected cells occurred with a significantly faster speed and to a greater extent than in CHO-WT cells. Additionally, C-1311 induced ROS generation in the two types of transfected cells, but not in CHO-WT cells. Moreover, CHO-HR-3A4 cells that did not die underwent accelerated senescence. Conclusion: CYP3A4 overexpression in CHO cells enhances apoptosis induced by C-1311, whereas the metabolism of C-1311 is minimal and does not depend on CYP3A4 expression.

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Section: Discussionmentioning

confidence: 99%

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

2013

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“…CYP3A4, which is expressed in ∼80% of breast cancer and correlated with decreased overall survival in breast cancer (47), was recently identified as an epoxygenase that catalyzes the conversion of ARA to EETs (48). Overexpression of CYP epoxygenases in cancer cells or endothelial cells accelerates tumor growth and metastasis (28,46,49), which are largely attributed to ARA-derived EETs (18).…”

Section: Discussionmentioning

confidence: 99%

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

Zhang

Panigrahy

Mahakian³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

262

264

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Epidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGFand fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg·kg −1 ·d −1 ) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ∼70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.

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“…Increased EET generation was linked, as in endothelial cells, to activation of the AMPK, JNK, and PI3-K/Akt signaling pathways, as well as increased EGFR phosphorylation levels (Chen et al, 2011a). However, whereas 11,12-EET is the isoform most frequently linked to endothelial cell angiogenesis, 14,15-EET was required for tumor cell proliferation and mechanistically attributed to Stat3 phosphorylation (Mitra et al, 2011).…”

Section: Inflammation and Resolution Of Inflammationmentioning

confidence: 99%

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

2014

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CYP3A4 Mediates Growth of Estrogen Receptor-positive Breast Cancer Cells in Part by Inducing Nuclear Translocation of Phospho-Stat3 through Biosynthesis of (±)-14,15-Epoxyeicosatrienoic Acid (EET)

Cited by 90 publications

References 43 publications

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

CYP3A4 overexpression enhances apoptosis induced by anticancer agent imidazoacridinone C-1311, but does not change the metabolism of C-1311 in CHO cells

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

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