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HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway
1Department of Molecular and Cellular Oncology, Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
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.
Insights
Overexpression of HER2/neu in cancer leads to resistance against tumor necrosis factor (TNF) by activating the Akt/NF-kappaB pathway. Blocking this pathway sensitizes cancer cells to TNF-induced apoptosis, enhancing immune defense against tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- HER2/neu overexpression is linked to poor survival in breast and ovarian cancers.
- HER2/neu confers resistance to tumor necrosis factor (TNF)-induced apoptosis, aiding cancer cell immune evasion.
- The molecular mechanisms underlying HER2/neu-mediated TNF resistance remain unclear.
Purpose of the Study:
- To elucidate the mechanism by which HER2/neu overexpression confers resistance to TNF.
- To investigate the role of the Akt and NF-kappaB signaling pathways in HER2/neu-induced TNF resistance.
Main Methods:
- Constitutive activation of Akt and NF-kappaB by HER2/neu was assessed without external stimulation.
- Dominant-negative Akt was used to block the Akt pathway in HER2/neu-overexpressing cells.
- Inhibition of IkappaB kinases, IkappaB phosphorylation, and NF-kappaB activation was measured.
Main Results:
- HER2/neu constitutively activates Akt and NF-kappaB signaling pathways.
- Blocking the Akt pathway sensitizes HER2/neu-overexpressing cells to TNF-induced apoptosis.
- Inhibition of the Akt pathway leads to reduced IkappaB kinase activity, IkappaB phosphorylation, and NF-kappaB activation.
Conclusions:
- HER2/neu constitutively activates the Akt/NF-kappaB anti-apoptotic cascade.
- This activation confers resistance to TNF, promoting cancer cell survival.
- Targeting the Akt/NF-kappaB pathway may restore TNF sensitivity and enhance anti-cancer immune responses.