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Oncotarget: Ibuprofen disrupts the protein complex in colon and rectal cells

Oncotarget data shed new light on the biochemical mechanisms behind ibuprofen’s action on the split-substitute RAC1B and may support its use in personalized approaches to treating CRC or chemoprophylaxis regimens.

Oncotarget Published “Ibuprofen inactivates the WNK1 / GSK3β / SRPK1 protein complex required to express the tumor-associated binding variant RAC1B in colorectal cells.Which reported that although the molecular mechanism behind the anti-tumor properties of NSAIDs is largely due to inhibition of cyclooxygenase, several studies have shown that the chemical protective properties of ibuprofen also include multiple COX-independent effects.

One example of this is its ability to inhibit the alternate splicing event generating RAC1B, which is overexpressed in a certain subset of BRAF-mutated colon and rectal tumors and maintains cell viability.

The authors describe here the mechanism by which ibuprofen prevents alternative splicing of RAC1B in a BRAF mutant CRC cell line: it reduces the transmission of SRPK1 and SRSF1 to the nucleus and is downregulated by the protein kinase complex WNK1 / GSK3β / SRPK1.

Surprisingly, they demonstrate that ibuprofen does not inhibit the activity of any of the kinases involved but rather promotes the degradation of this regulatory compound, and GSK3β exposes serine 9 to inhibitory phosphorylation, i.e. by AKT, which leads to nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation.

The Oncotarget The data sheds new light on the biochemical mechanisms behind ibuprofen’s action on the split RAC1B substitute and may support its use in personalized approaches to treating CRC or chemoprevention regimens.

The Oncotarget The data sheds new light on the biochemical mechanisms behind ibuprofen’s action on the split RAC1B substitute and may support its use in personalized approaches to treating CRC or chemoprevention regimens.

Dr. Peter Jordan of the National Institute of Health Dr. Ricardo George as well as the University of Lisbon said:Cancer is the second leading cause of death globally [1] A major risk factor for tumor development is chronic inflammation.

Long-term use of non-steroidal anti-inflammatory drugs, such as ibuprofen and aspirin, which are two of the most commonly prescribed medications worldwide, has been shown to provide chemoprophylaxis against various types of cancer.

Ibuprofen, like most NSAIDs, inhibits both isoforms of COX so that side effects such as gastrointestinal bleeding or cardiovascular disease can occur, raising the question of long-term use of NSAIDs for cancer chemoprophylaxis.

Interestingly, some NSAIDs have been reported to inhibit tumor growth by targeting other cellular processes and elucidation of basic biochemical processes can lead to the development of safer and more effective cancer chemoprevention or adjuvant drugs.

In the case of ibuprofen, several studies have shown that its chemopreventive properties are more complex and have many COX-independent effects.

The authors showed that ibuprofen disrupts the signal transduction pathway by unexpectedly interfering with the synthesis of the protein kinase complex, which consists of WNK1, GSK3β, and SRPK1. This leads to changes in the cellular localization of the binding factor SRSF1, which enhances inclusion of exon 3b in mRNA and the subsequent expression of RAC1B.

The Jordanian research team concluded in its Oncotarget research output,Our data indicate that ibuprofen treatment interferes with the signal transduction pathway involved in upregulating the split RAC1B substitute. The proposed model is schematically illustrated in Fig. 9. Another report of prostate cancer cells receiving combined treatment with ibuprofen and epigallocatechin-3-gallate, changes in alternative splicing have been reported, in particular the enhancement of BCL-X (S) or the shorter and shorter MCL . -1 (S) variables [43].

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DOI – https: //Resonate.Deer /10.18632 /oncotarget.27816

Full text – https: //www.oncotarget.Com /Article /27816 /Text /

Correspondence to – Peter Jordan – [email protected]

Key words
Ibuprofen,
Protein kinase,
RAC1B,
Alternative splicing,
Colon and rectal cancer cells

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