Peptide Aptamers with Binding Specificity for the Intracellular Domain of the ErbB2 Receptor Interfere with AKT Signaling and Sensitize Breast Cancer Cells to Taxol

• Published in: Molecular cancer research Vol. 4; no. 12; pp. 983 - 998
• Main Authors: Kunz, Christian, Borghouts, Corina, Buerger, Claudia, Groner, Bernd
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-12-2006
• Subjects: Amino Acid Motifs; Antineoplastic Agents - pharmacology; Aptamers, Peptide - chemistry; Aptamers, Peptide - pharmacology; breast cancer; Breast Neoplasms - pathology; chemotherapy; Drug Interactions; Drug Screening Assays, Antitumor; Humans; Intercellular Signaling Peptides and Proteins - pharmacology; interference with signaling components; Paclitaxel - pharmacology; peptide aptamers; Peptide Library; Protein Conformation; protein transduction; Proto-Oncogene Proteins c-akt - physiology; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Tumor Cells, Cultured
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-06-0046

The ErbB2 receptor tyrosine kinase is overexpressed in ∼30% of breast tumor cases and its overexpression correlates with an
unfavorable prognosis. A major contributor for this course of the disease is the insensitivity of these tumors toward chemotherapy.
Monoclonal antibodies, inhibiting the ligand-induced activation of the receptor and tyrosine kinase inhibitors acting on the
intrinsic enzymatic activity of the intracellular domain, have been developed as targeted drugs. Both have been shown to be
beneficial for breast cancer patients. We targeted a third aspect of receptor function: its association with intracellular
signaling components. For this purpose, we selected peptide aptamers, which specifically interact with defined domains of
the intracellular part of the receptor. The peptide aptamers were selected from a random peptide library using a yeast two-hybrid
system with the intracellular tyrosine kinase domain of ErbB2 as a bait construct. The peptide aptamer AII-7 interacts with
high specificity with the ErbB2 receptor in vitro and in vivo . The aptamers colocalized with the intracellular domain of ErbB2 within cells. We investigated the functional consequences
of the aptamer interaction with the ErbB2 receptor within tumor cells. The aptamer sequences were either expressed intracellularly
or introduced into the cells as recombinant aptamer proteins. The phosphorylation of p42/44 mitogen-activated protein kinase
was nearly unaffected and the activation of signal transducers and activators of transcription-3 was only modestly reduced.
In contrast, they strongly inhibited the induction of AKT kinase in MCF7 breast cancer cells treated with heregulin, whereas
AKT activation downstream of insulin-like growth factor I or epidermal growth factor receptor was not or only slightly affected.
High AKT activity is responsible for the enhanced resistance of ErbB2-overexpressing cancer cells toward chemotherapeutic
agents. Peptide aptamer interference with AKT activation resulted in the restoration of regular sensitivity of breast cancer
cells toward Taxol. (Mol Cancer Res 2006;4(12):983–98)