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
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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.
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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
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth