Abstract 1944: NFκB: Activation by EGF requires TLR4 and activation by LPS requires EGFR

Abstract

Abstract In normal cells, quiescent NFκB is activated by inflammatory stimuli, whereas the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. NFκB activation is regulated by several different pathways. Recently we showed that EGFR is an important mediator of NFκB activation, in both non-malignant and malignant cells. We now provide additional mechanistic insight into this pathway by further investigating whether signaling to NFκB in response to EGF depends solely on EGFR, or involves another receptor known to activate NFκB. Knockdown experiments revealed that TLR4 and two downstream components in the canonical TLR4 pathway, MYD88 and TAK1, are all required for EGF-dependent NFκB activation. Conversely, the ability of TLR4 to activate NFκB in response to LPS was impaired by down regulating EGFR expression or by use of the EGFR inhibitor erlotinib. PP2, a general inhibitor of SRC-family kinases, blocked EGF-induced NFκB activation, and the SRC family member LYN became bound to EGFR upon LPS stimulation. Erlotinib blocked this LPS-dependent association, indicating a key role for LYN in EGFR-TLR4 cross signaling. In mice, erlotinib blocked the LPS-induced, NFκB-dependent expression of TNFα and IL-6, indicating that EGFR is essential for LPS-induced NFκB activation in vivo. Citation Format: Sarmishtha De, Hao Zhou, Xiaoxia Li, George Stark. NFκB: Activation by EGF requires TLR4 and activation by LPS requires EGFR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1944. doi:10.1158/1538-7445.AM2015-1944