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RETRACTED ARTICLE: IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the func...

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Detalles Bibliográficos
Autores principales: Sasa, Keita, Saito, Tsuyoshi, Kurihara, Taisei, Hasegawa, Nobuhiko, Sano, Kei, Kubota, Daisuke, Akaike, Keisuke, Okubo, Taketo, Hayashi, Takuo, Takagi, Tatsuya, Yao, Takashi, Ishijima, Muneaki, Suehara, Yoshiyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8777567/
https://www.ncbi.nlm.nih.gov/pubmed/35201455
http://dx.doi.org/10.1007/s12672-021-00453-2
Descripción
Sumario:Osteosarcoma (OS) is the most common primary malignant bone tumor. However, the therapeutic results of the advanced cases at the first visit were still extremely poor. Therefore, more effective therapeutic options based on molecular profiling of OS are needed. In this study, we investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. The expression of 84 key genes associated with unfolded protein response (UPR) was assessed in four OS cells (143B, MG63, U2OS and KHOS) by RT2 Profiler PCR Arrays. Based on results, we performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. Furthermore, ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. On the other hand, IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth (IC50: < 0.075 μM) and cell viability was suppressed in all OS cell lines by silencing XBP1 expression. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. On the other hand, in 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. However, morphological apoptotic changes and caspase activation were observed in these two cell lines. Inhibition of the IRE1α-XBP1s pathway is expected to be a promising new target for OS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00453-2.