Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis.
Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis.
复制标题
DOI：
10.1002/jcb.22934
复制
发表时间：
2011-02
影响因子：
4
通讯作者：
Hei, Tom K.
中科院分区：
文献类型：
--
作者：
Ivanov, Vladimir N.;Partridge, Michael A.;Huang, Sarah X. L.;Hei, Tom K.
黑色素瘤是人类癌症中最致命的一种。然而，目前只有有限的化疗可用于疾病的转移阶段。由于化疗、放疗和亚砷酸钠治疗主要通过诱导内在线粒体途径发挥作用，因此转移性黑色素瘤细胞中线粒体功能的强烈下降可能是黑色素瘤常规治疗疗效低下的原因。转移性黑色素瘤细胞的另一个特征是其促炎表型，与炎性细胞因子（如TNFα IL 6和IL 8及其受体）的内源性表达以及组成性NF-κB和STAT 3依赖性基因表达（包括环氧合酶-2（PTGS 2/COX 2））相关。在本研究中，我们用免疫学（抗TNFα或IL 6的单克隆抗体）、药理学（IKKβ-NF-κB和JAK 2-STAT 3的小分子抑制剂）或遗传学（考克斯-2的特异性RNAi）药物治疗黑色素瘤细胞，这些药物抑制炎症反应，并通过TRAIL诱导细胞凋亡。作为这些联合治疗的结果，外源性TRAIL通过与TRAIL-R2/R1的相互作用强烈增加了抗性黑素瘤细胞中的凋亡水平。本研究为TRAIL介导的黑色素瘤细胞凋亡的调控提供了新的认识，并将为耐药黑色素瘤治疗的新方法的潜在发展奠定基础。
Melanoma is the most lethal form of human sk in 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 inmelanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas.
登录
查看更多内容
影响因子：
4.8
作者：
Ivanov, VN;Hei, TK
通讯作者：
Hei, TK
影响因子：
6.5
作者：
Hilmi, Caroline;Larribere, Lionel;Bertolotto, Corine
通讯作者：
Bertolotto, Corine
影响因子：
8
作者：
Ivanov, VN;Kehrl, JH;Ronai, Z
通讯作者：
Ronai, Z
影响因子：
11.2
作者：
Fulda, S;Debatin, KM
通讯作者：
Debatin, KM
影响因子：
8
作者：
Ivanov, VN;Hei, TK
通讯作者：
Hei, TK