title: IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress.
abstract: Osteosarcoma is a malignant bone tumor in children and adolescents characterized by intrinsic therapeutic resistance. The IGF2 is expressed at elevated levels in osteosarcoma after treatment with chemotherapy, prompting an examination of its functional contributions to resistance. We found that continuous exposure to IGF2 or insulin in the absence of serum created a dormant growth state in osteosarcoma cells that conferred resistance to various chemotherapeutic drugs in vitro. Mechanistic investigations revealed that this dormant state correlated with downregulation of downstream signaling by the IGF1 receptor, heightened cell survival, enhanced autophagy, and the presence of extracellular glutamine. Notably, inhibiting autophagy or depleting glutamine was sufficient to increase chemotherapeutic sensitivity in osteosarcoma xenografts in mice. Clinically, we confirmed that IGF expression levels were elevated in human osteosarcoma specimens from patients who received chemotherapy. Together, our results suggest that activation of IGF or insulin signaling preserves the survival of osteosarcoma cells under chemotherapeutic stress, providing a drug-resistant population that may engender minimal residual disease. Attenuating this survival mechanism may help overcome therapeutic resistance in osteosarcoma.
authors.affiliation: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan. Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. CREST, Japan Science and Technology Agency, Tokyo, Japan. t-shimizu@hoshi.ac.jp hsaya@a5.keio.jp.
authors.forename: Takatsune
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Yamaguchi-Iwai
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Tamaki
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Koyama
authors.affiliation: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan. Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Faculty of Science, Mansoura University, Mansoura, Egypt.
authors.forename: Walied
authors.initials: W
authors.lastname: Kamel
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Ueki
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Kasai R&D Center, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Chiyoda
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Osuka
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.affiliation: Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Junzo
authors.initials: J
authors.lastname: Kamei
authors.affiliation: Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fukuchi
authors.affiliation: Electron Microscopy Laboratory, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto, Japan. Department of Orthopaedic Surgery, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Toguchida
authors.affiliation: Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.affiliation: Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Muto
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. CREST, Japan Science and Technology Agency, Tokyo, Japan. t-shimizu@hoshi.ac.jp hsaya@a5.keio.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002648:Child; D019610:Cytoprotection; D019008:Drug Resistance, Neoplasm; D005260:Female; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology
chemical_list: D007328:Insulin; D005973:Glutamine; D007335:Insulin-Like Growth Factor II