Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells |
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| Institution: | 1. College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea;2. Department of Otolaryngology-Head and Neck Surgery, Center for Thyroid Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea;1. Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India;2. Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India;3. Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India;1. Institute of Biochemistry, Medical Faculty, Kiel University, Germany;2. CEITEC-Central European Institute of Technology, Masaryk University, Czech Republic;3. Institute of Molecular Pharmacology, University Hospital Aachen/RWTH, Aachen, Germany;1. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021, Guangxi, PR China;2. Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning 530001, Guangxi, PR China;3. Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning 530001, Guangxi, PR China;4. Department of Pharmacology, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi, PR China;5. Department of Pharmacy, The First People''s Hospital of Nanning, Nanning 530022, Guangxi, PR China;6. Department of Thoracic Tumor Surgery, Guangxi Cancer Hospital and Guangxi Medical University Affiliated Cancer Hospital, Nanning 530021, Guangxi, PR China;1. Cancer Research Program-12, Rajiv Gandhi Centre for Biotechnology (DBT-RGCB), Thycaud. P.O. Thiruvananthapuram-14, Kerala, India;2. Manipal Academy of Higher Education, Tiger Circle Road, Madhav Nagar, Manipal, Karnataka 576104, India;3. Neuro Stem Cell Biology Laboratory, Neurobiology Division, Rajiv Gandhi Centre for Biotechnology (DBT-RGCB), Thiruvananthapuram, Kerala 695 014, India;4. Regional Centre for Biotechnology (DBT-RCB), Faridabad, Haryana 121001, India |
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| 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. |
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