Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation.
Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation.
复制标题
NPe 6介导的光动力学治疗后胶质母细胞瘤细胞恶性表型的增强通过ERK 1/2激活进行调节。
DOI：
10.3390/cancers12123641
复制
发表时间：
2020-12-04
期刊：
影响因子：
5.2
通讯作者：
Tomiyama A
中科院分区：
文献类型：
--
作者：
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
在胶质母细胞瘤（GBM）中调节使用他拉泊芬钠（NPe6）（NPe6-PDT）的光动力疗法（PDT）抗性的分子机制以及NPe6-PDT后GBM表型变化的潜在机制仍然未知。在此，我们使用人GBM细胞系建立了体外NPe6介导的PDT模型。NPe6-PDT以NPe6剂量依赖性方式诱导半胱天冬酶依赖性和非依赖性GBM细胞死亡。此外，用聚（ADP-核糖）聚合酶抑制剂治疗阻断NPe6-PDT触发的半胱天冬酶非依赖性GBM细胞死亡。接着，发现在NPe6-PDT后存活的GBM细胞（NPe6-PDT-R细胞）对re-NPe6-PDT的抗性、迁移和侵袭增强。NPe6-PDT-R的免疫印迹显示，只有ERK 1/2活化表现出与迁移相同的趋势。重要的是，用MEK 1/2抑制剂trametinib治疗逆转了对re-NPe6-PDT的抗性，并抑制了NPe6-PDT-R细胞增强的迁移和侵袭。总之，增强的ERK 1/2活化被认为是NPe6-PDT存活的GBM细胞恶性表型升高的关键调节因子。为了管理难治性和侵袭性胶质母细胞瘤（GBM），使用他拉泊芬钠（NPe6）的光动力疗法（PDT）（NPe6-PDT）最近在临床实践中被批准。然而，GBM中调节NPe6-PDT抗性的分子机制和NPe6-PDT后GBM表型变化的潜在机制仍然未知。在此，我们使用人GBM细胞系建立了体外NPe6介导的PDT模型。NPe6-PDT以NPe6剂量依赖性方式诱导GBM细胞死亡。然而，这种NPe6-PDT诱导的GBM细胞死亡没有被泛半胱天冬酶抑制剂完全阻断，表明NPe6-PDT诱导半胱天冬酶依赖性和非依赖性细胞死亡。此外，用聚（ADP-核糖）聚合酶抑制剂治疗阻断NPe6-PDT触发的半胱天冬酶非依赖性GBM细胞死亡。接着，还揭示了GBM细胞和在NPe6-PDT后存活的GBM干细胞（NPe6-PDT-R细胞）对re-NPe6-PDT的抗性，以及NPe6-PDT-R细胞的迁移和侵袭增强。NPe6-PDT-R细胞的免疫印迹以评估已知为应激诱导的蛋白质的行为，揭示了仅ERK 1/2活化表现出与迁移相同的趋势。重要的是，用MEK 1/2抑制剂trametinib治疗逆转了对re-NPe6-PDT的抗性，并抑制了NPe6-PDT-R细胞增强的迁移和侵袭。总之，增强的ERK 1/2活化被认为是NPe6-PDT存活的GBM细胞恶性表型升高的关键调节因子，因此被认为是针对GBM的潜在治疗靶点。
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.
登录
查看更多内容
影响因子：
64.5
作者：
Lemmon MA;Freed DM;Schlessinger J;Kiyatkin A
通讯作者：
Kiyatkin A
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1002/ssu.2980020104
发表时间：
1986-01-01
期刊：
Seminars in Surgical Oncology
影响因子：
--
作者：
DOUGHERTY T J
通讯作者：
DOUGHERTY T J
影响因子：
3.7
作者：
Lamberti MJ;Pansa MF;Vera RE;Fernández-Zapico ME;Rumie Vittar NB;Rivarola VA
通讯作者：
Rivarola VA
由于溶酶体光损伤激活 Bax，细胞通过线粒体凋亡途径死亡
影响因子：
7.4
作者：
Liu, Lei;Zhang, Zhenzhen;Xing, Da
通讯作者：
Xing, Da