Abstract A86: LRP16, interacting with PKR, prolongs NF-kappaB activation and drives colorectal cancer tumorigenesis

NF-kappaB frequently activated in colorectal cancer (CRC) is linked to rapid malignant progression of CRC and is also crucial for the maintenance of homeostasis and therapy resistance. However, the underlying mechanisms how NF-kappaB activation and the crosstalk of NF-kappaB with other transcription factors are controlled in CRC remain incompletely understood. Here, we show that LRP16 physically interacts with double-stranded RNA-dependent protein kinase (PKR) functions as a signal transducer in signaling pathways activated by different stimuli by a variety of effectors, including NF-kappaB. Overexpression of LRP16 confers PKR autophosphorylation leading to the phosphorylation and activation of the NF-kappaB complex. Modulation of NF-kappaB mediated gene expression in response to diverse signals is coordinated by PKR through the phosphorylation and activation of IKK complex and this process does not require PKR kinase activity. We identified PKR, an essential regulatory subunit of the IKK complex. Silencing PKR expression by RNA interference blocked LRP16 induced expression of NF-kappaB target genes. These cells were also not protected from apoptosis in response to chemotherapy. In vivo, overexpression of LRP16 promotes CRC tumorigenesis, in turn, inhibition of LRP16 or PKR blunts CRC tumorigenesis. These results demonstrated that LRP16 likely functions by recruiting PKR to the IKK complex and thus serves a regulatory function for NF-kappaB activation, suggesting that a novel...

Source: Molecular Cancer Research - January 15, 2016 Category: Cancer & Oncology Authors: Li, X., Wu, Z., Han, W. Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research