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

Abstract 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 cellula...

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Autores principales:	Kohei Okuyama, Keiji Suzuki, Tomofumi Naruse, Hiroki Tsuchihashi, Souichi Yanamoto, Atsushi Kaida, Masahiko Miura, Masahiro Umeda, Shunichi Yamashita
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e696f56cecc94299aeb6208f2e259997
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spelling	oai:doaj.org-article:e696f56cecc94299aeb6208f2e2599972021-12-02T13:34:46ZProlonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma10.1038/s41598-021-84877-42045-2322https://doaj.org/article/e696f56cecc94299aeb6208f2e2599972021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84877-4https://doaj.org/toc/2045-2322Abstract 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 p27Kip1, 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.Kohei OkuyamaKeiji SuzukiTomofumi NaruseHiroki TsuchihashiSouichi YanamotoAtsushi KaidaMasahiko MiuraMasahiro UmedaShunichi YamashitaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kohei Okuyama Keiji Suzuki Tomofumi Naruse Hiroki Tsuchihashi Souichi Yanamoto Atsushi Kaida Masahiko Miura Masahiro Umeda Shunichi Yamashita Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
description	Abstract 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 p27Kip1, 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.
format	article
author	Kohei Okuyama Keiji Suzuki Tomofumi Naruse Hiroki Tsuchihashi Souichi Yanamoto Atsushi Kaida Masahiko Miura Masahiro Umeda Shunichi Yamashita
author_facet	Kohei Okuyama Keiji Suzuki Tomofumi Naruse Hiroki Tsuchihashi Souichi Yanamoto Atsushi Kaida Masahiko Miura Masahiro Umeda Shunichi Yamashita
author_sort	Kohei Okuyama
title	Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
title_short	Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
title_full	Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
title_fullStr	Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
title_full_unstemmed	Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma
title_sort	prolonged cetuximab treatment promotes p27kip1-mediated g1 arrest and autophagy in head and neck squamous cell carcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/e696f56cecc94299aeb6208f2e259997
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Prolonged cetuximab treatment promotes p27Kip1-mediated G1 arrest and autophagy in head and neck squamous cell carcinoma

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