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

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journal contribution
posted on 20.06.2016, 10:19 by C. Le Clorennec, Y. Lazrek, O. Dubreuil, C. Larbouret, M-A. Poul, P. Mondon, Gerry Melino, A. Pèlegrin, T. Chardès
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.

Funding

“Investissement d’Avenir” (grant agreement: Labex MabImprove, ANR-10-LABX-53-01) and by the grant AAP13 “Fonds Unique Interministeriel” FUI UmAbHER3 F120402M.

History

Citation

Oncotarget, Vol. 7, No. 24

Version

VoR (Version of Record)

Published in

Oncotarget

Publisher

Impact Journals

eissn

1949-2553

Acceptance date

16/04/2016

Available date

20/06/2016

Publisher version

http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=9455

Language

en

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