The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2-dependent ITCH/AIP4 activation

Christophe Le Clorennec, Yassamine Lazrek, Olivier Dubreuil, Christel Larbouret, Marie Alix Poul, Philippe Mondon, Gerry Melino, André Pèlegrin, Thierry Chardès

Research output: Contribution to journalArticle

Abstract

We characterized the mechanism of action of the neuregulin-non-competitive anti-HER3 therapeutic antibody 9F7-F11 that blocks the PI3K/AKT pathway, leading to cell cycle arrest and apoptosis in vitro and regression of pancreatic and breast cancer in vivo. We found that 9F7-F11 induces rapid HER3 down-regulation. Specifically, 9F7-F11-induced HER3 ubiquitination and degradation in pancreatic, breast and prostate cancer cell lines was driven mainly by the itchy E3 ubiquitin ligase (ITCH/AIP4). Overexpression of the ITCH/AIP4 inhibitor N4BP1 or small-interfering RNA-mediated knockdown of ITCH/AIP4 inhibited HER3 ubiquitination/degradation and PI3K/AKT signaling blockade induced by 9F7-F11. Moreover, 9F7-F11-mediated JNK1/2 phosphorylation led to ITCH/AIP4 activation and recruitment to HER3 for receptor ubiquitination and degradation. ITCH/AIP4 activity was activated by the deubiquitinases USP8 and USP9X, as demonstrated by RNA interference. Taken together, our results suggest that 9F7-F11-induced HER3 ubiquitination and degradation in cancer cells mainly occurs through JNK1/2-dependent ITCH/AIP4 activation.

Original languageEnglish
Pages (from-to)37013-37029
Number of pages17
JournalOncotarget
Volume7
Issue number24
DOIs
Publication statusPublished - 2016

Keywords

  • Antibody
  • Cancer
  • HER3
  • ITCH/AIP4
  • Treatment

ASJC Scopus subject areas

  • Oncology

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    Le Clorennec, C., Lazrek, Y., Dubreuil, O., Larbouret, C., Poul, M. A., Mondon, P., Melino, G., Pèlegrin, A., & Chardès, T. (2016). The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2-dependent ITCH/AIP4 activation. Oncotarget, 7(24), 37013-37029. https://doi.org/10.18632/oncotarget.9455