Secretariat, Alumni Association, IDAC
Date	Wednesday, 11 September 2019, 11:00～13:00
Room	7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research
Title	1. NOS2 and COX2 as major drivers of poor outcome in ER- breast cancer. New therapeutic opportunities in a difficult disease. 2. Reactive Species Interactions and the ‘Redox Interactome’ Lessons from a Journey in Adaptations to Stress
Speaker	1. 11:00-12:00 David A. Wink 2. 12:00-13:00 Martin Feelisch
Affiliation	1. Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health 2. Clinical & Experimental Sciences, Faculty of Medicine, Southampton General Hospital and Institute for Life Sciences, University of Southampton1.
Organizer	Hozumi Motohashi (Dept. Gene Expression Regulation・ext 8550)
Abstract	1. Pro-inflammatory signaling pathways are commonly up-regulated in breast cancer. In estrogen receptor-negative (ER-) and triple-negative breast cancer (TNBC), nitric oxide synthase-2 (NOS2) and cyclooxygenase-2 (COX2; PTGS2) are independent predictors of disease outcome. To investigate the effect of their co-expression on breast cancer survival, we analyzed tumors from 248 patients and found that their combined expression is associated with a dismal survival of ER- patients with less than 50% of them surviving 5 years post diagnosis. Furthermore, we found that the key metabolites of NOS2 and COX2, nitric oxide (NO) and prostaglandin E2 (PGE2), are drivers of the co-expression when we analyzed the NOS2-COX2-crosstalk in MDA-MB-468 (basal-like) and MDA-MB-231 (mesenchymal-like) TNBC cell lines. We identified a feed-forward relationship where NO induces COX2 and PGE2 induces NOS2. Induction of COX2 was dependent on the NO-mediated activation of TRAF2 which occurred in a TNFα-dependent manner in MB-468 cells. In contrast, TRAF2 activation involved the endoplasmatic reticulum stress response in MDA-MB-231 cells. Moreover, simultaneous inhibition of NOS2 and COX2 using aminoguanidine (AG) and aspirin yielded an additive reduction in growth of MDA-MB-231 tumor xenografts. Pathway analysis of patients that compared NOS2hi/COX2hi (25% survival) and NOS2lo/COX2lo (100% survival) patients revealed that pathways associated with IFNγ and IL-17. In vitro studies show that IFNγ in conjunction with IL17A/F but not IL17A/F alone dramatically increase NOS2/COX2 expression. Furthermore, IFNγ increased immunosuppressive markers PDL1 and IDO1 as well as ICAM-1 associated with metastasis in NO/PGE2 independent manner. These levels IFNγ required to activate these NOS2/COX dependent and independent pathways were considerably lower than those associated with therapeutic levels of IFNγ associated with antitumor immune response. Taken together, these results suggest that pathways associated with IFNγ play a role in NOS2/COX2 expression leading to a feed-forward interaction activating many critical oncogenic pathways that have been associated with the progression of ER- breast cancer and offers insight into the mechanism that causes poor survival of these patients. 2. One in four of us will require Critical Care at some stage of their life; of those admitted to the Intensive Care Unit of a hospital on average 40% will die. Important and costly patient management decisions are often based on very limited ‘hard data’, with little information on bodily function other than acute organ damage as well as cardiovascular/respiratory, renal/electrolyte and oxygenation status. Cellular hypoxia, with systemic inflammation, is a near ubiquitous challenge in this setting, and supplementary oxygen is given almost indiscriminately to treat lower arterial pO2. These conditions are associated with marked alterations in redox signalling but little is known that would be useful to guide treatment decisions, and research efforts are often limited by ethical considerations. An alternative approach is to study healthy individuals subjected to similar stresses in a more controlled fashion. This seminar will provide an overview of experimental insights gained from whole-body investigations at high altitude where hypoxia-related metabolic perturbations such as oxidative stress and inflammation are an inevitable feature. I will review some of the complexity of the molecular interactions of reactive oxygen, nitrogen and sulfur species with each other and their biological targets in the context of whole-body regulation in health and discuss how this may be altered in disease states and used to inform future treatment of the critically ill patient.