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

Srikumar M. Raja, Robert J. Clubb, Mitra Bhattacharyya, Manjari Dimri, Hao Cheng, Wei Pan, Cesar Ortega-Cava, Alagarsamy Lakku-Reddi, Mayumi Naramura, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

49 Citations (Scopus)

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™). Resistance to Trastuzumab and eventual failure in most cases, however, necessitate alternate ErbB2-targeted therapies. HSP90 inhibitors such as 17-allylaminodemethoxygeldanamycin (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.

Original languageEnglish (US)
Pages (from-to)1629-1639
Number of pages11
JournalCancer Biology and Therapy
Volume7
Issue number10
StatePublished - Oct 1 2008

Fingerprint

Breast Neoplasms
Down-Regulation
Therapeutics
Antibodies, Monoclonal, Humanized
Trastuzumab
Ubiquitin-Protein Ligases
Cell Death
Cell Line
Growth
Pharmaceutical Preparations

Keywords

  • 17-AAG
  • ErbB2
  • Synergy
  • Trastuzumab
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

A combination of trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells. / Raja, Srikumar M.; Clubb, Robert J.; Bhattacharyya, Mitra; Dimri, Manjari; Cheng, Hao; Pan, Wei; Ortega-Cava, Cesar; Lakku-Reddi, Alagarsamy; Naramura, Mayumi; Band, Vimla; Band, Hamid.

In: Cancer Biology and Therapy, Vol. 7, No. 10, 01.10.2008, p. 1629-1639.

Research output: Contribution to journalArticle

Raja, SM, Clubb, RJ, Bhattacharyya, M, Dimri, M, Cheng, H, Pan, W, Ortega-Cava, C, Lakku-Reddi, A, Naramura, M, Band, V & Band, H 2008, '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 and Therapy, vol. 7, no. 10, pp. 1629-1639.
Raja, Srikumar M. ; Clubb, Robert J. ; Bhattacharyya, Mitra ; Dimri, Manjari ; Cheng, Hao ; Pan, Wei ; Ortega-Cava, Cesar ; Lakku-Reddi, Alagarsamy ; Naramura, Mayumi ; Band, Vimla ; Band, Hamid. / A combination of trastuzumab and 17-AAG induces enhanced ubiquitinylation and lysosomal pathway-dependent ErbB2 degradation and cytotoxicity in ErbB2-overexpressing breast cancer cells. In: Cancer Biology and Therapy. 2008 ; Vol. 7, No. 10. pp. 1629-1639.
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