Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma

• Published in: Scientific reports 2021-03, Vol.11 (1), p.5259-5259, Article 5259
• Main Authors: Okuyama, Kohei, Suzuki, Keiji, Naruse, Tomofumi, Tsuchihashi, Hiroki, Yanamoto, Souichi, Kaida, Atsushi, Miura, Masahiko, Umeda, Masahiro, Yamashita, Shunichi
• Format: Article
• Language: English
• Subjects: 631/337; 631/67; 631/80; 692/4028; AKT protein; Autophagy; Cancer; Cell adhesion & migration; Cell cycle; Cell density; Cell migration; Cyclin-dependent kinase inhibitor p27; Epidermal growth factor; Epidermal growth factor receptors; G1 phase; Head & neck cancer; Humanities and Social Sciences; Immunotherapy; Monoclonal antibodies; Motility; multidisciplinary; Phagocytosis; Phosphorylation; Retina; Retinoblastoma; Science; Science (multidisciplinary); Skp2 protein; Squamous cell carcinoma; Targeted cancer therapy; TOR protein; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-84877-4

Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is an efficient anti-tumor therapeutic agent that inhibits the activation of EGFR; however, data related to the cellular effects of prolonged cetuximab treatment are limited. In this study, the long-term cellular outcome of prolonged cetuximab treatment and the related molecular mechanism were explored in a head and neck squamous cell carcinoma cell line constitutively expressing a fluorescent ubiquitination-based cell cycle indicator. Fluorescent time-lapse imaging was used to assess clonal growth, cell motility, and cell-cycle progression. Western blot analysis was performed to measure the level of phosphorylation and protein-expression following cetuximab treatment. Over 5 days cetuximab treatment decreased cell motility and enhanced G1 phase cell arrest in the central region of the colonies. Significantly decreased phosphorylation of retinoblastoma, Skp2, and Akt-mTOR proteins, accumulation of p27 Kip1 , and induction of type II LC3B were observed over 8 days cetuximab treatment. Results of the present study elucidate the cetuximab-dependent inhibition of cell migration, resulting in high cell density-related stress and persistent cell-cycle arrest at G1 phase culminating in autophagy. These findings provide novel molecular insights related to the anti-tumor effects of prolonged cetuximab treatment with the potential to improve future therapeutic strategy.