カワマタ　タカカズ   Kawamata Takakazu   川俣　貴一    所属   医学部 医学科（東京女子医科大学病院）    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation.
掲載誌名	正式名：Cancers 略　 称：Cancers (Basel) ISSNコード：20726694/20726694
掲載区分	国外
巻・号・頁	12(12),pp.3641
著者・共著者	KOBAYASHI Tatsuya†, MITAZAKI Makoto, SASAKI Nobuyoshi, YAMAMURO Shun, UCHIDA Eita, KAWAUCHI Daisuke, TAKAHASHI Masamichi, OTSUKA Yohei,, KUMAGAI Kosuke, TAKEUCHI Satoru, OTANI Naoki, WADA Kojiro, NARITA Yoshitaka, YAMAGUCHI Hideki, MURAGAKI Yoshihiro, KAWAMATA Takakazu, MORI Kentaro, ICHIMURA Koichi, TOMIYAMA Arata
発行年月	2020/12/04
概要	To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM.
DOI	10.3390/cancers12123641
PMID	33291680