Header

UZH-Logo

Maintenance Infos

Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNF in glioblastoma


Kusne, Y; Carrera-Silva, E A; Perry, A S; Rushing, E J; Mandell, E K; Dietrich, J D; Errasti, A E; Gibbs, D; Berens, M E; Loftus, J C; Hulme, C; Yang, W; Lu, Z; Aldape, K; Sanai, N; Rothlin, C V; Ghosh, S (2014). Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNF in glioblastoma. Science Signaling, 7(338):ra75.

Abstract

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.

Abstract

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer because resistance to these drugs often develops. We showed that tumor necrosis factor-α (TNFα) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFα-dependent activation of the transcription factor nuclear factor κB (NF-κB) and for tumor cell-intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor-resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.

Statistics

Citations

18 citations in Web of Science®
19 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

1 download since deposited on 13 Jan 2015
0 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:13 Jan 2015 15:52
Last Modified:22 Nov 2017 14:39
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
Publisher DOI:https://doi.org/10.1126/scisignal.2005196
PubMed ID:25118327

Download