A combination of Trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells

• DOI: 10.4161/cbt.7.10.6585
• Publication Date: 2010-05-26T15:16:43Z
• Authors: Srikumar M. Raja; Robert J. Clubb; Mitra Bhattacharyya; Manjari Dimri; Hao Cheng; Wei Pan; Cesar Ortega-Cava; Alagarsamy Lakku-...; Mayumi Naramura; Vimla Band; Hamid Band
• Keywords: Cell Death; Receptor, ErbB-2; Ubiquitin; Lactams, Macrocyclic; Antibodies, Monoclonal; Breast Neoplasms; Trastuzumab; Antibodies, Monoclonal, Humanized; Flow Cytometry; Models, Biological; Protein Structure, Tertiary; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Microscopy, Fluorescence; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Benzoquinones; Humans; HSP90 Heat-Shock Proteins; Lysosomes

AbstractErbB2 (or Her2/Neu) overexpression in breast cancer signifies poorer prognosis, yet it has provided an avenue for targeted therapy as demonstrated by the success of humanized monoclonal antibody Trastuzumab (Herceptin). Resistance to and eventual failure most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such 17-allylaminodemethoxygeldanamycin (17-AAG), potently downregulate cell surface ErbB2. While precise mechanisms or 17-AAG action remain unclear, ubiquitinylation-dependent proteasomal lysosomal degradation ErbB2 appears play a substantial role. As induce recruitment distinct E3 ubiquitin ligases, Cbl CHIP respectively, ErbB2, we hypothesized that combination could higher level ubiquitinylation downregulation compared single drug treatments. We present biochemical biological evidence combined treatment ErbB2-overexpressing lines leads enhanced ubiquitinylation, from Importantly, induced synergistic growth arrest death specifically but not ErbB2-low cells. Our results suggest mechanism-based combinatorial patients. Running title: