Watanabe Mariko, Umezawa Kazuo, Higashihara Masaaki, Horie Ryouichi
Department of Hematology, School of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan.
Oncol Res. 2013;21(4):173-80. doi: 10.3727/096504014X13887748696707.
Constitutive activation of nuclear factor κB (NF-κB) characterizes melanoma cells. To explore the molecular mechanism of melanoma cell survival by constitutive NF-κB activation, we used the NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which directly binds to NF-κB. DHMEQ abrogated constitutive NF-κB activity, which included RelA (p65)/p50 in melanoma cell lines G361 and HMV-II; however, the reduction of the viability was marginal. Expression of c-FLIP was not observed in the melanoma cell lines tested, and DHMEQ could not repress the expression of the Bcl-2 family proteins Bcl-2 and Bcl-xL. Concomitant treatment with DHMEQ and the inhibitor of antiapoptotic Bcl-2 family proteins, GX15-070, triggered synergistic reduction of the viability and induced apoptosis of G361 cells. These results indicate that abrogation of the NF-κB pathway alone is not sufficient to suppress the survival of melanoma cells. The NF-κB and the antiapoptotic Bcl-2 pathways cooperatively support the survival, and the dual targeting triggers synergistic reduction of the viability and induces apoptosis of melanoma cells.
核因子κB（NF-κB）的组成性激活是黑色素瘤细胞的特征。为了探究组成性NF-κB激活介导黑色素瘤细胞存活的分子机制，我们使用了直接与NF-κB结合的NF-κB抑制剂去羟甲基环氧喹霉素（DHMEQ）。DHMEQ消除了组成性NF-κB活性，这包括黑色素瘤细胞系G361和HMV-II中的RelA（p65）/p50；然而，细胞活力的降低幅度很小。在所测试的黑色素瘤细胞系中未观察到c-FLIP的表达，并且DHMEQ无法抑制Bcl-2家族蛋白Bcl-2和Bcl-xL的表达。DHMEQ与抗凋亡Bcl-2家族蛋白抑制剂GX15-070联合处理可协同降低G361细胞的活力并诱导其凋亡。这些结果表明，单独消除NF-κB途径不足以抑制黑色素瘤细胞的存活。NF-κB和抗凋亡Bcl-2途径协同支持细胞存活，双重靶向可协同降低黑色素瘤细胞的活力并诱导其凋亡。
