HER-2/neu Blocks Tumor Necrosis Factor-induced Apoptosis via the Akt/NF-κB Pathway

作者：Binhua Peter Zhou, Mickey C.‐T. Hu, Stephanie A. Miller, Zhenming Yu, Weiya Xia, Shiaw‐Yih Lin, Mien‐Chie Hung · 发表于：Journal of Biological Chemistry · 年份：2000 · DOI：10.1074/jbc.275.11.8027 · 被引用次数：373 · 研究领域：NF-κB Signaling Pathways、Cytokine Signaling Pathways and Interactions、Cell death mechanisms and regulation

Overexpression of HER-2/neu correlates with poor survival of breast and ovarian cancer patients and induces resistance to tumor necrosis factor (TNF), which causes cancer cells to escape from host immune defenses. The mechanism of HER-2/neu-induced TNF resistance is unknown. Here we report that HER-2/neu activates Akt and NF-kappaB without extracellular stimulation. Blocking of the Akt pathway by a dominant-negative Akt sensitizes the HER-2/neu-overexpressing cells to TNF-induced apoptosis and inhibits IkappaB kinases, IkappaB phosphorylation, and NF-kappaB activation. Our results suggested that HER-2/neu constitutively activates the Akt/NF-kappaB anti-apoptotic cascade to confer resistance to TNF on cancer cells and reduce host defenses against neoplasia.