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Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells
Ilju Kim1, Pattawika Lertpatipanpong1, Yongdae Yoon1
1College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea.
Abstract:
Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3β protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.
Insights
Tolfenamic acid (TA) reduces cancer-promoting YAP and TAZ proteins by increasing their degradation. This NSAID targets specific sites, offering a novel approach to inhibit tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- The Hippo pathway, regulated by YAP and TAZ proteins, is crucial for controlling cell proliferation and cancer metastasis.
- Overactivation of YAP and TAZ accelerates tumor growth, invasion, and migration.
Purpose of the Study:
- To investigate the effect of Tolfenamic acid (TA) on YAP and TAZ protein levels in cancer cells.
- To elucidate the mechanism by which TA influences YAP and TAZ activity and degradation.
Main Methods:
- Treatment of cancer cells with Tolfenamic acid (TA).
- Analysis of YAP and TAZ protein levels, phosphorylation status, and degradation pathways.
- Assessment of 14-3-3β protein expression and ubiquitination.
- Investigation of the role of NAG-1 and E3 ligases in TA-mediated degradation.
Main Results:
- TA significantly decreased YAP and TAZ protein levels in cancer cells.
- TA treatment led to increased YAP and TAZ phosphorylation, promoting their degradation.
- TA affected multiple phosphodegron sites on YAP/TAZ and reduced 14-3-3β expression, facilitating ubiquitination.
- TA-mediated YAP/TAZ degradation did not involve NAG-1 or known YAP/TAZ E3 ligases.
Conclusions:
- Tolfenamic acid (TA) exhibits a novel mechanism of action against cancer by targeting YAP and TAZ phosphodegron sites.
- TA promotes YAP/TAZ degradation, offering a potential therapeutic strategy for cancers driven by aberrant Hippo pathway signaling.
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