Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer.

Abstract

Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3'-digallate (TFBG) is identified as an inhibitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.

• Authors: Wengui Shi, Gengyuan Zhang, Zhijian Ma, Lianshun Li, Miaomiao Liu, Long Qin, Zeyuan Yu, Lei Zhao, Yang Liu, Xue Zhang, Junjie Qin, Huili Ye, Xiangyan Jiang, Huinian Zhou, Hui Sun, Zuoyi Jiao
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 2812 (05 14 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 33990570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Immunological
• Biflavonoids
• Cell Cycle Proteins
• MISP protein, human
• Microfilament Proteins
• Phosphoproteins
• Proto-Oncogene Proteins
• SHCBP1 protein, human
• Shc Signaling Adaptor Proteins
• theaflavin-3,3'-digallate
• Catechin
• ERBB2 protein, human
• Receptor, ErbB-2
• Protein Serine-Threonine Kinases
• polo-like kinase 1
• Trastuzumab

Topics

• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Biflavonoids (pharmacology)
• Catechin (analogs & derivatives, pharmacology)
• Cell Cycle Proteins (chemistry, metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Drug Resistance, Neoplasm (physiology)
• Female
• Gene Knockdown Techniques
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Mice
• Microfilament Proteins (metabolism)
• Middle Aged
• Mitosis (drug effects)
• Models, Biological
• Models, Molecular
• Phosphoproteins (metabolism)
• Prognosis
• Protein Interaction Domains and Motifs (drug effects)
• Protein Serine-Threonine Kinases (chemistry, metabolism)
• Proto-Oncogene Proteins (chemistry, metabolism)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Shc Signaling Adaptor Proteins (antagonists & inhibitors, chemistry, metabolism)
• Signal Transduction (drug effects)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Trastuzumab (pharmacology)
• Xenograft Model Antitumor Assays