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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-11, Vol.74 (22), p.6531-6541
• Main Authors: Shimizu, Takatsune, Sugihara, Eiji, Yamaguchi-Iwai, Sayaka, Tamaki, Sakura, Koyama, Yuko, Kamel, Walied, Ueki, Arisa, Ishikawa, Tomoki, Chiyoda, Tatsuyuki, Osuka, Satoru, Onishi, Nobuyuki, Ikeda, Hiroko, Kamei, Junzo, Matsuo, Koichi, Fukuchi, Yumi, Nagai, Toshihiro, Toguchida, Junya, Toyama, Yoshiaki, Muto, Akihiro, Saya, Hideyuki
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Animals; Autophagy - physiology; Bone Neoplasms - drug therapy; Bone Neoplasms - pathology; Cell Line, Tumor; Cell Survival; Child; Cytoprotection; Drug Resistance, Neoplasm; Female; Glutamine - metabolism; Humans; Insulin - pharmacology; Insulin-Like Growth Factor II - analysis; Insulin-Like Growth Factor II - pharmacology; Male; Mice; Mice, Inbred C57BL; Osteosarcoma - drug therapy; Osteosarcoma - pathology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-0914

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.