Neratinib induces ErbB2 ubiquitylation and endocytic degradation via HSP90 dissociation in breast cancer cells.
Receptor tyrosine kinase ErbB2/HER2 is frequently observed to be overexpressed in human cancers, leading to over activation of downstream signaling modules. HER2 positive is a major type of breast cancer for which ErbB2 targeting is already proving to be an effective therapeutic strategy. Apart from antibodies against ErbB2, the small molecule tyrosine kinase inhibitor lapatinib has had successful clinical outcomes, and other inhibitors such as neratinib are currently undergoing clinical investigations. In this study we report the effects of lapatinib and neratinib on the mRNA and protein levels of the ErbB2 receptor. We provide evidence that neratinib-induced down regulation of ErbB2 occurs through ubiquitin-mediated endocytic sorting and lysosomal degradation. At the mechanistic level, neratinib treatment leads to HSP90 release from ErbB2 and its subsequent ubiquitylation and endocytic degradation. Our findings provide novel insights into the mechanism of ErbB2 inhibition by neratinib.
Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Yingqiu
Y
Zhang
Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Jinrui
J
Zhang
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Cancer Biotherapy & Translational Medicine Center of Liaoning Province, Dalian Medical University, Dalian, China.
Congcong
C
Liu
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Sha
S
Du
Department of Pathology, First Affiliated Hospital, Dalian Medical University, Dalian, China.
Lu
L
Feng
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Xuelin
X
Luan
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Yayun
Y
Zhang
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Yulin
Y
Shi
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Taishu
T
Wang
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Yue
Y
Wu
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Wei
W
Cheng
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Songshu
S
Meng
Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. Electronic address: liman126126@163.com.
Man
M
Li
Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; Cancer Biotherapy & Translational Medicine Center of Liaoning Province, Dalian Medical University, Dalian, China. Electronic address: liuhan@dlmedu.edu.cn.
Han
H
Liu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination / Q000187:drug effects*
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C487932:neratinib
Breast cancer; Endocytosis; ErbB2; HER2; Neratinib; Ubiquitylation