Abstract
A major risk factor promoting tumor development is chronic inflammation and the use of nonsteroidal anti-inflammatory drugs (NSAID), including ibuprofen, can decrease the risk of developing various types of cancer, including colorectal cancer (CRC). Although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases (COXs), several studies have shown that the chemopreventive properties of ibuprofen also involve multiple COX-independent effects. One example is its ability to inhibit the alternative splicing event generating RAC1B, which is overexpressed in a specific subset of BRAF-mutated colorectal tumors and sustains cell survival. Here we describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant CRC cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3β/SRPK1 protein kinase complex. Surprisingly, we demonstrate that ibuprofen does not inhibit the activity of any of the involved kinases but rather promotes disassembly of this regulatory complex, exposing GSK3β serine 9 to inhibitory phosphorylation, namely by AKT, which results in nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation. The data shed new light on the biochemical mechanisms behind ibuprofen’s action on alternative spliced RAC1B and may support its use in personalized approaches to CRC therapy or chemoprevention regimens.
Highlights
Cancer is the second leading cause of death globally [1] and one major risk factor for tumor development is chronic inflammation [2]
We describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant colorectal cancer (CRC) cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3β/SRPK1 protein kinase complex
These results suggest that ibuprofen inhibits RAC1B splicing through alterations in the phosphorylation state of SRSF1 and in its subcellular localization
Summary
Cancer is the second leading cause of death globally [1] and one major risk factor for tumor development is chronic inflammation [2]. COX-1 isoform is constitutively expressed in most tissues and the prostaglandins it produces have physiological roles in the maintenance of the gastric mucosa, blood vessel regulation and kidney function [9] Another isoform, COX-2, is induced during the inflammatory response but more persistently expressed under pathological conditions including chronic inflammation and cancer [10]. Numerous studies have shown that its cancer chemopreventive properties are much more complex and involve multiple COX-independent effects [8] These can act through various cell cycleand apoptosis-regulating pathways, including β-catenin, NF-κB, and p53, leading to changes in gene expression [12]. Even small changes in RAC1B protein levels will generate a predominantly GTP-loaded and signaling competent conformation that preferentially stimulates the transcription factor NF-κB and is required to sustain cell survival in BRAF mutant CRC cells [16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
