Insulin-like growth factor I receptor regulates the radiation-induced G2/M checkpoint in HeLa cells

Journal Article · Sat Sep 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.08.080· OSTI ID:23103597

Manila, Nisha Gowri; Kaida, Atsushi ^[1]; Nakahama, Ken-ichi ^[2]; Miura, Masahiko ^[1]

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1. Department of Oral Radiation Oncology, Division of Oral Health Sciences (Japan)
2. Department of Cellular Physiological Chemistry, Division of Maxillofacial and Neck Reconstruction, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549 (Japan)

Highlights: • Inhibition of IGF-IR elongated radiation-induced G2 arrest in HeLa cells. • Inhibition of PI3K or AKT, but not MEK, induced the same effect. • IGF-IR inhibition did not essentially affect DSB repair kinetics. • Radiation-induced CHK1 nuclear localization lasted longer in IGF-IR-inhibited cells. • IGF-IR may regulate G2/M checkpoint in part via CHK1 shuttling within the cell. Insulin-like growth factor I receptor (IGF-IR) plays pivotal roles in various biological events, including cell growth, transformation, survival, and DNA repair. In this study, we explored its possible involvement in cell cycle checkpoints, using HeLa cells expressing the fluorescent ubiquitination-based cell cycle indicator (Fucci). We found that IGF-IR inhibitor delayed release from radiation-induced G2 arrest, as demonstrated by FACS and pedigree analysis of Fucci fluorescence. Elongated G2 arrest was also induced by inhibitors of phosphatidylinositol-3 kinase (PI3K) and AKT, but not by inhibitor of MEK, which are two major IGF-IR downstream signaling pathways. Double-strand break (DSB) repair kinetics were not affected by IGF-IR inhibitor. CHK1 inhibitor abrogated radiation-induced G2 arrest, whereas radiation-induced phosphorylation of CHK1 at Ser 345 or Ser 296 was decreased by the IGF-IR inhibitor. However, radiation-induced nuclear localization of CHK1 was prolonged in IGF-IR inhibitor–treated cells in comparison with cells that received radiation alone; in the latter, CHK1 returned to the original diffuse distribution in conjunction with release from G2 arrest. We conclude that IGF-IR directly regulates the G2/M checkpoint via the PI3K/AKT pathway without influencing DSB repair, in part by controlling CHK1 localization between the nucleus and cytoplasm.

• OSTI ID: 23103597
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 503; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL CYCLE
DNA REPAIR
FLUORESCENCE
GROWTH FACTORS
HELA CELLS
INSULIN
PHOSPHORYLATION