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Article

Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation

1
Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2
Department of Neurosurgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan
3
Department of Neurosurgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
4
Faculty of Advanced Techno-Surgery, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
5
Department of Cancer Cell Research, Sasaki Institute, Sasaki Foundation, 2-2 Kandasurugadai Chiyoda-ku, Tokyo 101-0062, Japan
6
Department of Neurosurgery, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
7
Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Ohyaguchi, Kamicho, Itabashi-Ku, Tokyo 173-8610, Japan
8
Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka-City, Saitama 350-1298, Japan
9
Department of Neurological Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8677, Japan
10
Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
11
Department of Neurosurgery, Tokyo General Hospital, Tokyo 165-8906, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3641; https://doi.org/10.3390/cancers12123641
Received: 26 October 2020 / Revised: 27 November 2020 / Accepted: 29 November 2020 / Published: 4 December 2020
(This article belongs to the Special Issue Recurrent Glioblastoma)
The molecular machineries regulating resistance against photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) in glioblastomas (GBM)s 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 both caspase-dependent and -independent GBM cell death in a NPe6 dose-dependent manner. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was revealed resistance to re-NPe6-PDT, migration, and invasion of GBM cells that survived following NPe6-PDT (NPe6-PDT-R cells) were enhanced. Immunoblotting of NPe6-PDT-R 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.
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. View Full-Text
Keywords: photodynamic therapy; talaporfin; resistance; migration; ERK1/2; glioblastoma photodynamic therapy; talaporfin; resistance; migration; ERK1/2; glioblastoma
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MDPI and ACS Style

Kobayashi, T.; Miyazaki, M.; Sasaki, N.; Yamamuro, S.; Uchida, E.; Kawauchi, D.; Takahashi, M.; Otsuka, Y.; Kumagai, K.; Takeuchi, S.; Toyooka, T.; Otani, N.; Wada, K.; Narita, Y.; Yamaguchi, H.; Muragaki, Y.; Kawamata, T.; Mori, K.; Ichimura, K.; Tomiyama, A. Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation. Cancers 2020, 12, 3641. https://doi.org/10.3390/cancers12123641

AMA Style

Kobayashi T, Miyazaki M, Sasaki N, Yamamuro S, Uchida E, Kawauchi D, Takahashi M, Otsuka Y, Kumagai K, Takeuchi S, Toyooka T, Otani N, Wada K, Narita Y, Yamaguchi H, Muragaki Y, Kawamata T, Mori K, Ichimura K, Tomiyama A. Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation. Cancers. 2020; 12(12):3641. https://doi.org/10.3390/cancers12123641

Chicago/Turabian Style

Kobayashi, Tatsuya, Makoto Miyazaki, Nobuyoshi Sasaki, Shun Yamamuro, Eita Uchida, Daisuke Kawauchi, Masamichi Takahashi, Yohei Otsuka, Kosuke Kumagai, Satoru Takeuchi, Terushige Toyooka, Naoki Otani, Kojiro Wada, Yoshitaka Narita, Hideki Yamaguchi, Yoshihiro Muragaki, Takakazu Kawamata, Kentaro Mori, Koichi Ichimura, and Arata Tomiyama. 2020. "Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation" Cancers 12, no. 12: 3641. https://doi.org/10.3390/cancers12123641

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