Nanlou Department of Neurology, Chinese PLA General Hospital, Beijing, PR China.
Cancer Lett. 2012 Jan 28;314(2):137-46. doi: 10.1016/j.canlet.2011.09.022. Epub 2011 Oct 1.
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.
放射疗法是头颈部癌症（HNC）治疗的一种重要手段。丝裂原活化蛋白激酶磷酸酶-1（MKP-1）蛋白水平在各种肿瘤中升高，与化疗或放疗的疗效呈负相关。然而，HNC 中度放射敏感性和 MKP-1 蛋白水平升高的机制仍不清楚。在这里，我们表明 MKP-1 上半胱氨酸 258 的 S-亚硝基化增强了 MKP-1 蛋白的稳定性、磷酸酶活性以及 MKP-1 对 HNC 放射治疗的抗凋亡作用。用激活的巨噬细胞共培养转染了 MKP-1 的 HNC 细胞系，以模拟受照射癌细胞的微环境，进一步证实了 S-亚硝基化介导的 MKP-1 活性增加与 HNC 放射敏感性降低相关。因此，MKP-1 的 S-亚硝基化是头颈部癌症中增强的 MKP-1 表达水平和 MKP-1 介导的放射抵抗的新机制。
