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

Abstract 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...

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Autores principales:	Keita Sasa, Tsuyoshi Saito, Taisei Kurihara, Nobuhiko Hasegawa, Kei Sano, Daisuke Kubota, Keisuke Akaike, Taketo Okubo, Takuo Hayashi, Tatsuya Takagi, Takashi Yao, Muneaki Ishijima, Yoshiyuki Suehara
Formato:	article
Lenguaje:	EN
Publicado:	Springer 2021
Materias:	Osteosarcoma ER stress IRE1α-XBP1 pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/85b9019b871845f2aaa55cdf3b4a35f5
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spelling	oai:doaj.org-article:85b9019b871845f2aaa55cdf3b4a35f52021-12-05T12:26:29ZIRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma10.1007/s12672-021-00453-22730-6011https://doaj.org/article/85b9019b871845f2aaa55cdf3b4a35f52021-11-01T00:00:00Zhttps://doi.org/10.1007/s12672-021-00453-2https://doaj.org/toc/2730-6011Abstract 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.Keita SasaTsuyoshi SaitoTaisei KuriharaNobuhiko HasegawaKei SanoDaisuke KubotaKeisuke AkaikeTaketo OkuboTakuo HayashiTatsuya TakagiTakashi YaoMuneaki IshijimaYoshiyuki SueharaSpringerarticleOsteosarcomaER stressIRE1α-XBP1 pathwayNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENDiscover Oncology, Vol 12, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Osteosarcoma ER stress IRE1α-XBP1 pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Osteosarcoma ER stress IRE1α-XBP1 pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Keita Sasa Tsuyoshi Saito Taisei Kurihara Nobuhiko Hasegawa Kei Sano Daisuke Kubota Keisuke Akaike Taketo Okubo Takuo Hayashi Tatsuya Takagi Takashi Yao Muneaki Ishijima Yoshiyuki Suehara IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
description	Abstract 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.
format	article
author	Keita Sasa Tsuyoshi Saito Taisei Kurihara Nobuhiko Hasegawa Kei Sano Daisuke Kubota Keisuke Akaike Taketo Okubo Takuo Hayashi Tatsuya Takagi Takashi Yao Muneaki Ishijima Yoshiyuki Suehara
author_facet	Keita Sasa Tsuyoshi Saito Taisei Kurihara Nobuhiko Hasegawa Kei Sano Daisuke Kubota Keisuke Akaike Taketo Okubo Takuo Hayashi Tatsuya Takagi Takashi Yao Muneaki Ishijima Yoshiyuki Suehara
author_sort	Keita Sasa
title	IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
title_short	IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
title_full	IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
title_fullStr	IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
title_full_unstemmed	IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
title_sort	ire1α-xbp1 but not perk inhibition exerts anti-tumor activity in osteosarcoma
publisher	Springer
publishDate	2021
url	https://doaj.org/article/85b9019b871845f2aaa55cdf3b4a35f5
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IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma

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