Theaflavins target Fas/caspase-8 and Akt/pBad pathways to induce apoptosis in p53-mutated human breast cancer cells.

摘要: The most common alterations found in breast cancer are inactivation or mutation of tumor suppressor gene p53. present study revealed that theaflavins induced p53-mutated human cell apoptosis. Pharmacological inhibition caspase-8 expression dominant-negative (Dn)-caspase-8/ Fas-associated death domain (FADD) partially inhibited apoptosis, whereas caspase-9 inhibitor completely blocked the killing indicating involvement parallel pathways converged to mitochondria. Further studies demonstrated theaflavin-induced Fas upregulation through activation c-jun N-terminal kinase, Fas―FADD interaction a ligand-independent manner, and t-Bid formation. A search for pathway survival pathway, mediated by Akt deactivation Bcl-xLBcl-2-associated promoter dephosphorylation. These well-defined routes growth control process mitochondrial transmembrane potential loss, cytochrome c release executioner -3. Overexpression either constitutively active myristylated-Akt (Myr-Akt) Dn-caspase-8 permeability transition apoptosis cells, cotransfection Myr-Akt abolished theaflavin effect thereby negating possibility existence third pathways. results other biochemical correlates established concept two distinct signaling were regulated induce cascade, eventually culminating cells strongly resistant conventional therapies.