ABSTRACT
SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.
Subject(s)
Immunomodulation , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Melanoma/etiology , Melanoma/metabolism , Sirtuin 2/metabolism , Animals , Biomarkers , Cell Line, Tumor , Cell Movement , Disease Progression , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Lymphocytes, Tumor-Infiltrating/pathology , Melanoma/pathology , Melanoma, Experimental , Mice , Sirtuin 2/genetics , Tumor Microenvironment/genetics , Tumor Microenvironment/immunologyABSTRACT
Mammalian Sphingosine kinase 2 is the primary enzyme responsible for phosphorylating FTY720 to its active form, FTY720-P. Systemic FTY720 treatment confers significant protection to murine retinas from light- and disease-mediated photoreceptor cell death. It is not clear whether FTY720-P, FTY720, or both are responsible for this photoreceptor protection. We investigated Sphingosine kinase 2 knockout (Sphk2 KO) mouse retinas, tested their sensitivity to light, and measured what degree of protection from light-induced damage they receive from systemic FTY720 treatment. Sphk2 KO retinas were found to be similar to their wild-type counterparts in sensitivity to light damage. Additionally, FTY720 treatment protected Sphk2 KO retinas from light-induced damage despite significant retardation of FTY720 phosphorylation in Sphk2 KO mice. We conclude that FTY720 serves an active role in preventing photoreceptor cell death. Furthermore, we conclude that the phosphorylation of FTY720 is not necessary to provide this protective effect.
Subject(s)
Fingolimod Hydrochloride/pharmacology , Light , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Retina/metabolism , Sphingosine 1 Phosphate Receptor Modulators/pharmacology , Animals , Mice , Mice, Knockout , Phosphorylation/drug effects , Phosphotransferases (Alcohol Group Acceptor)/genetics , Retina/drug effects , Retina/injuriesABSTRACT
PURPOSE: To assess the frequency and risk factors for intraoperative anesthesia consultation when performing cataract surgery monitored by registered nurses. SETTING: Iowa City Veterans Affairs Medical Center, Iowa City, Iowa, USA. METHODS: This retrospective review was of 270 cataract surgeries performed under local anesthesia from April 1, 2002, to April 1, 2003. RESULTS: The American Society of Anesthesiologists (ASA) classification of each patient was determined: 1 patient was classified as ASA 1. One hundred fifty patients were classified as ASA 2. One hundred nineteen patients were classified as ASA 3. The anesthesiology department was consulted 24 times. Nineteen consultations involved patients who were ASA 3, and 5 consultations involved patients who were ASA 2 (P<.001). In most cases (23 of 24), the anesthesia service provided a consultation (eg, increase oxygen flow rate, clarification of electrocardiogram, start intravenous line, equipment repair) and left the nurses to continue to monitor the patient. In only 1 case (ASA 3), the anesthesia service converted the case to monitored anesthesia care and relieved the nurse to monitor the patient. CONCLUSIONS: In this study, monitoring of routine cataract surgery by registered nurses was associated with a low rate of intraoperative anesthesia consultation. Most consultations resulted in little intervention. The ASA classification appears predictive of the need for intraoperative anesthesia consultation.
