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Comment
. 2017 Dec 26;114(52):13591-13593.
doi: 10.1073/pnas.1717440114. Epub 2017 Dec 13.

NO and COX2: Dual targeting for aggressive cancers

Daniel Davila-Gonzalez  1 , Jenny C Chang  1 , Timothy R Billiar  2
Affiliations
Comment

NO and COX2: Dual targeting for aggressive cancers

Daniel Davila-Gonzalez et al. Proc Natl Acad Sci U S A. .
No abstract available

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Chronic levels of NO promote inflammation and tumorigenesis. NO is primarily generated by NOS2 from the cancer cells; however, immune, endothelial and stromal cells also produce NO. In ER− breast cancer, NO production is driven by a NOS2/COX2 cross-talk. NO activates an inflammatory cascade that produces an up-regulation of COX2, increasing levels of PGE2. Similarly, PGE2 also promotes the synthesis of NOS2. Two different pathways (green) are commonly activated by NO: TNF-α/TRAF2//cJun/MAPK/COX2, and c-Src/PI3K/cJun/COX2. In Basal A Er− breast cancer cell lines (purple), NF-κβ is also involved in the activation of Fra1/cJun, causing COX2 activation. In aggressive Basal B subtype (gray), IRE1α promotes the activation of MAPK. COX2 activation phosphorylates pAKT S847 that inactivates proapoptotic BAD and CAS9 activation. Both NOS2 and COX2 activate the secretion of IL-8, IL-6, and GM-CSF to sustain tumor microenvironment. Other enzymes from NOX, COX, and LOX families also produce free radicals like NO, which translate in different signals such as tumor maintenance, proliferation, and survival. NOS2 (blue) and COX2 (yellow) co-overexpression is a risk factor for poor prognosis in ER− breast cancer patients (HR = 21.2, 95% CI: 2.78–161.9, P = 0.003).
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