IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress

被引：82

作者：

Shimizu, Takatsune ^{[1
,2
,3
]}

Sugihara, Eiji ^{[2
,3
]}

Yamaguchi-Iwai, Sayaka ^{[2
,4
]}

Tamaki, Sakura ^{[5
]}

Koyama, Yuko ^{[5
]}

Kamel, Walied ^{[1
,6
,7
]}

Ueki, Arisa ^{[2
]}

Ishikawa, Tomoki ^{[2
,8
]}

Chiyoda, Tatsuyuki ^{[2
]}

Osuka, Satoru ^{[2
]}

Onishi, Nobuyuki ^{[2
]}

Ikeda, Hiroko ^{[9
]}

Kamei, Junzo ^{[9
]}

Matsuo, Koichi ^{[6
]}

Fukuchi, Yumi ^{[1
]}

Nagai, Toshihiro ^{[10
]}

Toguchida, Junya ^{[5
,11
,12
]}

Toyama, Yoshiaki ^{[4
]}

Muto, Akihiro ^{[1
]}

Saya, Hideyuki ^{[2
,3
]}

机构：

[1] Hoshi Univ, Sch Pharm & Pharmaceut Sci, Dept Pathophysiol, Shinagawa Ku, Tokyo 1428501, Japan

[2] Keio Univ, Sch Med, Inst Adv Med Res, Div Gene Regulat,Shinjuku Ku, Tokyo, Japan

[3] Japan Sci & Technol Agcy, CREST, Tokyo, Japan

[4] Keio Univ, Sch Med, Dept Orthoped Surg, Shinjuku Ku, Tokyo, Japan

[5] Kyoto Univ, Inst Frontier Med Sci, Dept Tissue Regenerat, Sakyo Ku, Kyoto, Japan

[6] Keio Univ, Sch Med, Lab Cell & Tissue Biol, Shinjuku Ku, Tokyo, Japan

[7] Mansoura Univ, Fac Sci, Mansoura 35516, Egypt

[8] Daiichi Sankyo Co Ltd, Kasai R&D Ctr, Tokyo, Japan

[9] Hoshi Univ, Dept Pathophysiol & Therapeut, Sch Pharm & Pharmaceut Sci, Shinagawa Ku, Tokyo 142, Japan

[10] Keio Univ, Sch Med, Electron Microscopy Lab, Shinjuku Ku, Tokyo, Japan

[11] Kyoto Univ, Ctr iPS Cell Res & Applicat, Dept Cell Growth & Differentiat, Sakyo Ku, Kyoto, Japan

[12] Kyoto Univ Hosp, Dept Orthopaed Surg, Sakyo Ku, Kyoto 606, Japan

来源：

CANCER RESEARCH | 2014年 / 74卷 / 22期

关键词：

STEM-CELLS; INSULIN; RESISTANCE; PHOSPHORYLATION; IDENTIFICATION; CONTRIBUTES; INHIBITION; QUIESCENCE; THERAPY;

D O I：

10.1158/0008-5472.CAN-14-0914

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2014 AACR.

引用

页码：6531 / 6541

页数：11

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