期刊
SCIENCE SIGNALING
卷 7, 期 338, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005196
关键词
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资金
- NIH [R01 CA149258, P30CA023074, ABRC 8-101, R01 AI089824, R01 NS082745, R01 CA175391, T32CA009213]
- CONICET Postdoctoral Fellowship
- Achievement Rewards for College Scientists Foundation Scholar Award
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-alpha (TNF alpha) 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 TNF alpha-dependent activation of the transcription factor nuclear factor kappa B (NF-kappa B) 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.
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