S-Nitrosylation of mitogen activated protein kinase phosphatase-1 suppresses radiation-induced apoptosis.
Radiotherapy is a key modality for head and neck cancer (HNC) treatment. Mitogen activated protein kinase phosphatase-1 (MKP-1) protein levels are elevated in various tumors and are negatively correlated with efficacy of chemo- or radio-therapy. However, the mechanisms underlying the moderate radiosensitivity of HNC and the increased MKP-1 protein levels are still dismal. Here we show that S-nitrosylation of MKP-1 on Cysteine 258 enhances MKP-1 protein stability, phosphatase activity, and MKP-1-mediated anti-apoptotic effect on HNC radiotherapy. Co-culturing MKP-1 transfected HNC cell lines with activated macrophages for mimicking the microenvironment of the irradiated cancer cells further confirms that S-nitrosylation-mediated increase of MKP-1 activity correlates with decrease of HNC radiosensitivity. Therefore, S-nitrosylation of MKP-1 presents a novel mechanism underlying the enhanced MKP-1 expression levels and MKP-1-mediated radio-resistance in head and neck cancer.
Nanlou Department of Neurology, Chinese PLA General Hospital, Beijing, PR China.
Weiping
W
Guan
Jibin
J
Sha
Xiaojuan
X
Chen
Yaling
Y
Xing
Jinqi
J
Yan
Zhaoqing
Z
Wang
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D005720:Gamma Rays; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011836:Radiation Tolerance
D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse