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Cancer Res. 2014 Nov 15;74(22):6531-41. doi: 10.1158/0008-5472.CAN-14-0914. Epub 2014 Oct 1.

IGF2 preserves osteosarcoma cell survival by creating an autophagic state of dormancy that protects cells against chemotherapeutic stress.

Author information

1
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.
2
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.
3
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.
4
Department of Tissue Regeneration, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
5
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.
6
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
7
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.
8
Department of Pathophysiology and Therapeutics, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
9
Laboratory of Cell and Tissue Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
10
Department of Pathophysiology, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan.
11
Electron Microscopy Laboratory, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
12
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.
13
Department of Orthopedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
14
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.

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.

PMID:
25273088
DOI:
10.1158/0008-5472.CAN-14-0914
[Indexed for MEDLINE]
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