Antitumor effects of novel shorter truncated insulin-like growth factor I receptors

Abstract

We generated novel truncated insulin-like growth factor I receptors (IGF-IRs) designated as 126/STOP, 223/STOP and 325/STOP in order to establish shorter soluble IGF-IRs than previously reported 486/STOP without abrogating the same antitumor effects. Stable transfection of 223/STOP and 325/STOP, but not 126/STOP caused inhibition of anchorage-independent growth of CaOV-3 ovarian cancer cells in vitro. This antitumor effect was reproduced when we used recombinant proteins of these constructs, suggesting a bystander effect of these shorter truncated IGF-IRs. Tumorigenesis in vivo of CaOV-3 cells tranfected with 223/STOP or 325/STOP was strictly inhibited, and inoculation of these cells in nude mice caused massive apoptosis exclusively in vivo. Phosphorylations of IGF-IR and Akt, but not Erk were attenuated in 223/STOP- or 325/STOP-transfected CaOV-3 cells, and downregulations of IGF-IR and Akt phosphorylation seemed to play at least a partial role in the anti-tumor effect of these novel truncated IGF-IRs. Since 223/STOP and 325/STOP are smaller in size than previously reported 486/STOP, and they retain the same antitumor effects, they could be good candidates for clinical application in the future.

Keywords: :

• AKT
• IGF-IR
• anti-tumor effect
• apoptosis
• bystander effect
• truncated mutant

Acknowledgments

We thank Dr. Sanetaka Shirahata (Graduate School of Genetic Resources Technology, Kyusyu University) for providing CHO-Ras cells, and Dr. Yasushi Adachi (First Department of Internal Medicine, Sapporo Medical University) for a fruitful discussion. This study was supported in part by Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan 13671719 and 16591661 (A.H.). Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan 13671719 and 16591661.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.