Oncotarget published "Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells" which reported that although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases , 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 the authors 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, they 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 Oncotarget 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.
Cancer is the second leading cause of death globally and one major risk factor for tumor development is chronic inflammation."
Dr. Peter Jordan, The National Health Institute, Dr. Ricardo Jorge, The University of Lisbon
A long term use of nonsteroidal anti-inflammatory drugs, like ibuprofen and aspirin, which are among the most commonly prescribed medications worldwide, was shown to provide chemoprevention against various types of cancer.
Ibuprofen, like most NSAIDs, inhibits both COX isoforms so that side-effects such as intestinal bleeding or cardiovascular disease can occur, questioning the long-term use of NSAIDs for cancer chemoprevention.
Interestingly, some NSAIDs were reported to inhibit tumor growth by targeting other cellular processes and elucidation of the underlying biochemical processes could lead to the development of safer and more efficacious drugs for cancer chemoprevention or adjuvant therapy.
In the case of ibuprofen, numerous studies have shown that its cancer chemopreventive properties are much more complex and involve multiple COX-independent effects.
The authors show that ibuprofen disrupts a signal transduction pathway by, unexpectedly, interfering with the assembly of a protein kinase complex, composed by WNK1, GSK3β and SRPK1. This leads to changes in the subcellular localization of splicing factor SRSF1, which promotes inclusion of exon 3b into the mRNA and subsequent expression of RAC1B.
The Jordan Research Team concluded in their Oncotarget Research Output, "our data suggest that ibuprofen treatment interferes with a signal transduction pathway involved in the regulation of alternative spliced RAC1B. The proposed model is schematically depicted in Figure 9.
One other report on prostate cancer cells receiving combined treatment of ibuprofen and epigallocatechin-3-gallate, reported changes in alternative splicing, in particular promoting the shorter and proapoptotic BCL-X (S) or MCL-1(S) variants .
Gonçalves, V., et al. (2020) Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells. Oncotarget. doi.org/10.18632/oncotarget.27816.