RETRACTED ARTICLE: IRE1α-XBP1 but not PERK inhibition exerts anti-tumor activity in osteosarcoma
Authors: Tatsuya Takagi
Tsuyoshi Saito
Yoshiyuki Suehara
Kei Sano
Taisei Kurihara
Keisuke Akaike
Daisuke Kubota
Muneaki Ishijima
Keita Sasa
Taketo Okubo
Takuo Hayashi
Takashi Yao
Nobuhiko Hasegawa
Journal: Discover Oncology (2021)
Discipline: CLINICAL MEDICINE
Keywords: ER stress; IRE1α-XBP1 pathway; Osteosarcoma.
Affiliations: Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan., Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan., Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan. ., Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. ., Department of Medicine for Orthopaedics and Motor Organ, Juntendo University School of Medicine, Tokyo, Japan. .

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: &lt; 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. 

Retracted: Yes

PubPeer comments:
 Retracted [25 March 2022] . --------------- The Editor in Chief has retracted this article. Concerns were raised after publication, and subsequent post publication peer review concluded that there was insufficient experimental work for this article. Therefore, the Editor in Chief has lost confidence in the results of the study. The authors have been offered to submit a revised manuscript for further peer review. Tsuyoshi Saito, Keita Sasa, Taisei Kurihara, Daisuke Kubota, and Muneaki Ishijima agree to this retraction. Nobuhiko Hasegawa, Kei Sano, Keisuke Akaike, Taketo Okubo, Takuo Hayashi, Tatsuya Takagi, Takashi Yao, and Yoshiyuki Suehara have not responded to any correspondence from the editor about this retraction. ,