Journal article
A combination of trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells
Cancer biology & therapy, v 7(10), pp 1629-1639
01 Oct 2008
PMID: 18769124
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
ErbB2 (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 the humanized monoclonal antibody Trastuzumab (Herceptin (TM)). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylam-inodemethoxygeldanamycin (17-AAG), potently downregulate the cell surface ErbB2. While the precise mechanisms of Trastuzumab or 17-AAG action remain unclear, ubiquitinylation-dependent proteasomal or lysosomal degradation of ErbB2 appears to play a substantial role. As Trastuzumab and 17-AAG induce the recruitment of distinct E3 ubiquitin ligases, Cbl and CHIP respectively, to ErbB2, we hypothesized that 17-AAG and Trastuzumab combination could induce a higher level of ubiquitinylation and downregulation of ErbB2 as compared to single drug treatments. We present biochemical and cell biological evidence that combined 17-AAG and Trastuzumab treatment of ErbB2-overexpressing breast cancer cell lines leads to enhanced ubiquitinylation, downregulation from the cell surface and lysosomal degradation of ErbB2. Importantly, combined 17-AAG and Trastuzumab treatment induced synergistic growth arrest and cell death specifically in ErbB2-overexpressing but not in ErbB2-low breast cancer cells. Our results suggest the 17-AAG and Trastuzumab combination as a mechanism-based combinatorial targeted therapy for ErbB2-overexpressing breast cancer patients.
Metrics
Details
- Title
- A combination of trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells
- Creators
- Srikumar M. Raja - University of Nebraska Medical CenterRobert J. Clubb - College Station Medical CenterMitra Bhattacharyya - Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USAManjari Dimri - Evanston NW Healthcare Res Inst, Evanston, IL USAHao Cheng - MIT, Dept Chem Engn, Cambridge, MA 02139 USAWei Pan - Mécanique et Engrenage ModerneCesar Ortega-Cava - College Station Medical CenterAlagarsamy Lakku-Reddi - Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USAMayumi Naramura - College Station Medical CenterVimla Band - College Station Medical CenterHamid Band - College Station Medical Center
- Publication Details
- Cancer biology & therapy, v 7(10), pp 1629-1639
- Publisher
- Taylor & Francis
- Number of pages
- 11
- Grant note
- DAMD17-02-1-0303; DAMD17-02-1-0508; W81XWH-05-1-0231; W81XWH-07-1-0351 / DOD Breast Cancer Research; United States Department of Defense Avon Breast Cancer Fund R01CA081076 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Jean Ruggles-Romoser Chair of Cancer Research Northwestern University NCI 1U54 CA119341-01 / NCI Center for Cancer Nanotechnology Excellence; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA CA 116552; 99900; CA99163; CA 87986; CA76118; CA94143; CA96844; CA81076 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Duckworth Family Chair of Breast Cancer Research
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Materials Science and Engineering
- Web of Science ID
- WOS:000260263600022
- Scopus ID
- 2-s2.0-54349098717
- Other Identifier
- 991021886372104721
UN Sustainable Development Goals (SDGs)
This publication has contributed to the advancement of the following goals:
InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology