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Apoptosis caused by chemotherapeutic inhibition of nuclear factor-kappaB activation
Debajit K Biswas1, Katherine J Martin, Cliona McAlister
1Dana-Farber Cancer Institute, Department of Cancer Biology, Boston, Massachusetts 02115, USA. Debajit_Biswas@dfci.harvard.edu
Abstract:
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.
Insights
Blocking nuclear factor kappa B (NF-κB) activation with targeted therapies can inhibit breast cancer growth and promote apoptosis. This approach shows promise for developing new breast cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor (EGF) signaling promotes breast cancer growth.
- Nuclear factor kappa B (NF-κB) is a key mediator of EGF-induced tumor cell proliferation and survival.
Purpose of the Study:
- To investigate the efficacy of inhibiting NF-κB activation in treating EGF-responsive breast cancer.
- To identify molecular mechanisms underlying NF-κB inhibition in breast cancer cells.
Main Methods:
- Treatment of mammary tumors in mice with protein kinase C (alpha/beta) inhibitor Go6976 or dominant-negative NF-κB inhibitor kinase mutants.
- Assessment of tumor growth, NF-κB activation (DNA-binding, nuclear translocation), and apoptosis.
- Gene expression profiling using cDNA microarray analysis.
Main Results:
- Inhibition of NF-κB activation blocked tumor growth and induced regression in mice.
- Treatments suppressed EGF-induced NF-κB activation and promoted apoptosis in cultured mammary tumor cells.
- Gene expression analysis revealed reversal of EGF-induced changes, including upregulation of proapoptotic genes and downregulation of antiapoptotic genes.
Conclusions:
- Targeting NF-κB activation is a practical strategy for EGF-responsive breast cancer chemotherapy.
- Reinstating apoptosis by blocking NF-κB offers a potential therapeutic avenue for breast cancer treatment.