Binding mode analysis of zerumbone to key signal proteins in the tumor necrosis factor pathway
Ayesha Fatima1, Ahmad Bustamam Hj Abdul2, Rasedee Abdullah3
1UPM-MAKNA Cancer Research Laboratory, Institute of Biosciences, University Putra Malaysia, 43400 Serdang, Malaysia. ayeshafatima.69@gmail.com.
Abstract:
Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis.
Insights
Zerumbone, derived from Zingiber zerumbet, shows potential in breast cancer treatment by inducing apoptosis. It inhibits key proteins in the tumor necrosis factor (TNF) pathway, including IKKβ and NF-κB, to halt cancer cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer is a leading global cancer in women.
- The tumor necrosis factor (TNF) pathway plays a complex role in cancer progression.
- Zerumbone, a sesquiterpene from Zingiber zerumbet, modulates TNF signaling.
Purpose of the Study:
- To investigate zerumbone's mechanism of action in breast cancer.
- To determine zerumbone's interaction with key proteins in the TNF pathway.
- To assess zerumbone's potential to induce apoptosis in cancer cells.
Main Methods:
- Computational analysis of zerumbone binding to TNF pathway proteins.
- In vitro studies examining effects on IKKβ and NF-κB.
- Assessment of apoptosis induction and cell proliferation inhibition.
Main Results:
- Zerumbone demonstrated significant binding affinity to TNF, IKKβ, and NF-κB.
- Zerumbone inhibits IKKβ kinase activity, preventing NF-κB activation.
- Zerumbone directly binds to the NF-κB complex, downregulating proliferation.
Conclusions:
- Zerumbone induces apoptosis in breast cancer cells via the TNF pathway.
- Inhibition of IKKβ and NF-κB by zerumbone offers a potential therapeutic strategy.
- Zerumbone's ability to target cytoplasmic proteins highlights its promise in cancer treatment.
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