Study of inhibition effect of herceptin on interaction between heregulin and erbB receptors HER3/HER2 by single-molecule force spectroscopy.
Herceptin is a monoclonal antibody against HER2, which is a member of the epidermal growth factor receptor (ErbB) family and is overexpressed in many cancers. In this work, we have applied single-molecule force spectroscopy to study the effect of Herceptin on HER2 modulated ligand-receptor interaction for ErbB signaling in living cells. Heregulin beta1 (HRG), the specific ligand of HER3, was used for HER2 activation as HER3 is the preferable dimerization partner of HER2 and HER3/HER2 is the most representative heterodimer found in cancer. Our results demonstrated a more stable binding of HRG to the cells co-expressing HER3 and HER2 than those expressing HER3 alone. Moreover, the binding force of Herceptin and HER2 is as strong as that of HRG and HER3/HER2. With the addition of Herceptin, the binding strength of HRG to the cells co-expressing HER3 and HER2 decreased. The presence of Herceptin changed the dynamic force spectrum of HRG-HER3/HER2 to that similar to HRG-HER3. Therefore, the enhancement in HRG-HER3 binding after recruiting HER2 was inhibited by Herceptin. The method offers a new approach to study the molecular mechanism of Herceptin anti-cancer effect.
Shi
Xiaoli
X
Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
Xu
Li
L
Yu
Junping
J
Fang
Xiaohong
X
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D006801:Humans; D008024:Ligands; D018625:Microscopy, Atomic Force / Q000379:methods*; D009369:Neoplasms / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013057:Spectrum Analysis / Q000379:methods*; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D008024:Ligands; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C087230:heregulin beta1