Riluzole-induced apoptosis in osteosarcoma is mediated through Yes-associated protein upon phosphorylation by c-Abl Kinase
| Autor: | Syeda M Azeem, Rifat Hasnat, Linda Wong, Salina Yan, Yesmin Chowdhury, Shraddha ChandThakuri, Iffat Tariq, Shahana S. Mahajan, Yu Qi Huang, Angelina Blyufer, Sonam Lhamo, Raquel Zhagui, Lucas Cecilio, Cassey Tam, Marian Raghubir, Chowdhury Nowshin Rahman |
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| Rok vydání: | 2021 |
| Předmět: |
Cytoplasm
Cell biology Cell Survival Molecular biology Science Apoptosis Bone Neoplasms Biochemistry Article Cell Line Tumor medicine Humans Tyrosine Phosphorylation Proto-Oncogene Proteins c-abl neoplasms bcl-2-Associated X Protein Cancer Cell Nucleus Gene knockdown Osteosarcoma Multidisciplinary ABL Riluzole Kinase Chemistry Drug discovery Biological techniques Tumor Protein p73 YAP-Signaling Proteins medicine.disease Gene Expression Regulation Neoplastic Protein Transport Gene Knockdown Techniques Cancer research Medicine medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Our lab has previously demonstrated Riluzole to be an effective drug in inhibiting proliferation and inducing apoptosis in both human and mouse osteosarcoma. Yes-associated protein is a transcription co-activator, known to be involved in cell proliferation or apoptosis depending on its protein partner. In the present study we investigated the role of YAP in apoptosis in osteosarcoma, we hypothesized that YAP may be activated by Riluzole to induce apoptosis in osteosarcoma. By knocking down the expression of YAP, we have demonstrated that Riluzole failed to induce apoptosis in YAP deficient osteosarcoma cells. Riluzole caused translocation of YAP from the cytoplasm to the nucleus, indicating YAP’s role in apoptosis. Both Riluzole-induced phosphorylation of YAP at tyrosine 357 and Riluzole-induced apoptosis were blocked by inhibitors of c-Abl kinase. In addition, knockdown of c-Abl kinase prevented Riluzole-induced apoptosis in LM7 cells. We further demonstrated that Riluzole promoted interaction between YAP and p73, while c-Abl kinase inhibitors abolished the interaction. Subsequently, we demonstrated that Riluzole enhanced activity of the Bax promoter in a luciferase reporter assay and enhanced YAP/p73 binding on endogenous Bax promoter in a ChIP assay. Our data supports a novel mechanism in which Riluzole activates c-Abl kinase to regulate pro-apoptotic activity of YAP in osteosarcoma. |
| Databáze: | OpenAIRE |
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