We've updated our Privacy Policy to make it clearer how we use your personal data.

We use cookies to provide you with a better experience. You can read our Cookie Policy here.

Advertisement
Ibuprofen Disrupts Key Protein Complex in Colorectal Cancer Cells
News

Ibuprofen Disrupts Key Protein Complex in Colorectal Cancer Cells

Ibuprofen Disrupts Key Protein Complex in Colorectal Cancer Cells
News

Ibuprofen Disrupts Key Protein Complex in Colorectal Cancer Cells

Credit: Vnukko/ Pixabay
Read time:
 

Want a FREE PDF version of This News Story?

Complete the form below and we will email you a PDF version of "Ibuprofen Disrupts Key Protein Complex in Colorectal Cancer Cells"

First Name*
Last Name*
Email Address*
Country*
Company Type*
Job Function*
Would you like to receive further email communication from Technology Networks?

Technology Networks Ltd. needs the contact information you provide to us to contact you about our products and services. You may unsubscribe from these communications at any time. For information on how to unsubscribe, as well as our privacy practices and commitment to protecting your privacy, check out our Privacy Policy

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.

Dr. Peter Jordan from The National Health Institute Dr. Ricardo Jorge as well as The University of Lisbon said, "Cancer is the second leading cause of death globally [1] and one major risk factor for tumor development is chronic inflammation."

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.

Reference: Gonçalves V, Henriques AFA, Matos P, Jordan P. Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells. Oncotarget. 2020;11(47):4421-4437. doi: 10.18632/oncotarget.27816

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Advertisement