Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Cell Biochem. 2011 Feb;112(2):463-75. doi: 10.1002/jcb.22934.
Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKβ-NF-κB and JAK2-STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas.
黑色素瘤是最致命的人类皮肤癌形式。然而，目前对于该疾病的转移性阶段，仅有有限的化疗可供使用。由于化疗、放疗和亚砷酸钠治疗主要通过诱导内在的线粒体途径起作用，转移性黑色素瘤细胞中线粒体功能的严重降低，可能是导致黑色素瘤常规治疗效果不佳的原因。转移性黑色素瘤细胞的另一个特征是其促炎表型，与内源性表达的炎症细胞因子（如 TNFα、IL6 和 IL8）、其受体以及组成型 NF-κB 和 STAT3 依赖性基因表达（包括环氧化酶-2（PTGS2/COX2））有关。在本研究中，我们用免疫（针对 TNFα 或 IL6 的单克隆抗体）、药理学（IKKβ-NF-κB 和 JAK2-STAT3 的小分子抑制剂）或遗传（COX-2 的特异性 RNAi）手段处理黑色素瘤细胞，这些手段抑制了炎症反应并通过 TRAIL 诱导了细胞凋亡。由于这些联合治疗，通过 TRAIL-R2/R1 相互作用的外源性 TRAIL 大大增加了耐药黑色素瘤细胞中凋亡的水平。本研究提供了对 TRAIL 介导的黑色素瘤细胞凋亡调控的新认识，并将为开发耐药性黑色素瘤治疗的新方法奠定基础。
