Ayesha Fatima
Pharmacist, Malaysia
Title: Zerumbone modulation of the beta-catenin-TCF4 binding to induce apoptosis in cancer cells
Biography
Biography: Ayesha Fatima
Abstract
The Wnt-beta catenin pathway has been explored in several cancers. Aberration in the beta catenin inhibitory complex is thought to be the major cause for its uninhibited nuclear translocation and proliferation of cancer cells. Zerumbone, a sesquiterpene from Zingiber zerumbet Smith., has shown an excellent effectiveness as anticancer by inducing apoptosis in a time-dependent and concentration-dependent manner. Using computational techniques, this study aimed to predict the targets of Zerumbone in the pathway and to understand their binding mechanism. Our results showed that beta catenin-TCF4 complex could be the targets of Zerumbone. The binding free energy of beta catenin-TCF4 complexes from docking and molecular mechanics are -80 kcal/mol and -11. 9 kcal/mol, respectively. QM/MM method was used to estimate the effect of binding dynamics in the critical binding area between beta catenin-TCF4. It was found that the binding free energy was -29 kcal/mol in the QM region. From the results of steered molecular dynamics, the force required to pull the TCF4 peptide from the beta catenin in the presence of Zerumbone was almost similar, however it took slightly longer time to pull the chain. Wet laboratory results also confirmed that Zerumbone inhibits beta catenin nuclear translocation in HEPG2 cell line, however same results were not observed for MCF7. Hence, Zerumbone can strongly modulate the binding of beta catenin with TCF4 in a time-dependent manner thus altering the cellular pool of cell proliferating proteins. Further analysis still requires to unveil the mechanisms of the inhibition process of beta catenin and TCF4-DNA complex.