Biswas Debajit K, Martin Katherine J, McAlister Cliona, Cruz Antonio P, Graner Edgard, Dai Sun-chun, Pardee Arthur B
Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, Massachusetts 02115, USA.
Cancer Res. 2003 Jan 15;63(2):290-5.
Both the protein kinase C (alpha/beta) inhibitor Go6976 and expression of dominant-negative nuclear factor (NF)-kappaB inhibitor kinase mutants: (a) blocked the growth and caused regression of a mammary tumor insyngeneic mice; (b) inhibited epidermal growth factor (EGF)-induced activation, nuclear translocation, and DNA-binding activity of NF-kappaB; and (c) caused apoptosis of EGF-stimulated cultured mammary tumor cells. cDNA microarray analysis revealed that these treatments reversed the expression changes of a subset of genes altered by EGF treatment. These included: up-regulation of proapoptotic genes of the tumor necrosis factor (TNF) pathway, death-associated protein (DAP) kinase, p53, and p21/Waf1; and down-regulation of inhibitors of apoptosis: inhibitor of apoptosis(IAP)-1 and X-IAP, TNF receptor-associated factor (TRAF)-2, and factors OX40 and 4-1BB. These results and our previous studies suggest the practicality of a target-directed chemotherapy for EGF-responsive breast cancers, by blocking NF-kappaB activation and thereby reinstating apoptosis.
蛋白激酶C（α/β）抑制剂Go6976以及显性负性核因子（NF）-κB抑制激酶突变体的表达均：（a）阻断了同基因小鼠乳腺肿瘤的生长并使其消退；（b）抑制了表皮生长因子（EGF）诱导的NF-κB激活、核转位及DNA结合活性；（c）导致了EGF刺激的培养乳腺肿瘤细胞凋亡。cDNA微阵列分析显示，这些处理逆转了EGF处理所改变的一部分基因的表达变化。这些基因包括：肿瘤坏死因子（TNF）途径的促凋亡基因、死亡相关蛋白（DAP）激酶、p53和p21/Waf1的上调；凋亡抑制因子的下调：凋亡抑制蛋白（IAP）-1和X-IAP、TNF受体相关因子（TRAF）-2以及OX40和4-1BB因子。这些结果以及我们之前的研究表明，通过阻断NF-κB激活从而恢复凋亡，对EGF反应性乳腺癌进行靶向化疗具有可行性。
