Elucidation of the Molecular Mechnism of Aglaia Elliptifolia Extract Rocaglamide Induced Cell Death in Breast Cancer Cells---PHB as a Target

Cancer is the major cause of death worldwide, and breast cancer is the 4th leading cause of cancer death in Taiwan. Treatment of breast cancer becomes challenge when metastasis is development. We found several potent markers, which could be served as the drug targets in invasive ductal carcinoma, including prohibitin (PHB). PHB plays oncogenic roles in breast cancer, and overexpression of PHB on plasma membrane promotes cell migratory activity. Rocaglamide A (RocA) isolated from Aglaia elliptifolia by Taiwan researches has been reported to target PHB protein-protein interaction domain, which provides physical interaction with RAF1 and modulate oncogenic RAS/RAF/MEK/ERK signaling. Our previous findings also demonstrated that RocA exhibits potent anticancer activities by reducing cell proliferation, inducing cell cycle arrest, inhibiting cell migration, downregulating epithelial-mesenchymal transition, activating autophagy pathway, and triggering apoptotic cell death. However, the detailed molecular mechanism, especially in signaling transduction pathways, RocA takes remains unclear. To expand the understanding of the effects of RocA in breast cancer cells, the major objective of this proposal is to elucidate the RocA induced phosphorylation-mediated pathways as the molecular basis for improving breast cancer therapy. The specific aims are 1. To study the effects of RocA on RAS/RAF/MEK/ERK signaling in breast cancer cells in presence and in absence of surface localized PHB. (Year 1) 2. To discover how RocA induced autophagy and apoptosis in breast cancer cells. (Year 1~2) 3. To elucidate RocA altered phosphorylation signaling in breast cancer cells relaying on RAS/RAF/MEK/ERK pathway. (Year 2~3) 4. To construct the RocA induced kinase-substrate associated network (KSAN) in breast cancer, and to verify the RocA triggered KSAN in vitro. (Year 3~4) 5. To examine the efficacy of RocA by xenograft models and to verify the RocA triggered KSAN in vitro and in vivo. (Year 4)