SerpinB3 drives cancer stem cell survival in glioblastoma.
SerpinB3 drives cancer stem cell survival in glioblastoma.
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DOI：
10.1016/j.celrep.2022.111348
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发表时间：
2022-09-13
期刊：
影响因子：
8.8
通讯作者：
Lathia, Justin D.
中科院分区：
文献类型：
--
作者：
Lauko, Adam;Volovetz, Josephine;Turaga, Soumya M.;Bayik, Defne;Silver, Daniel J.;Mitchell, Kelly;Mulkearns-Hubert, Erin E.;Watson, Dionysios C.;Desai, Kiran;Midha, Manav;Hao, Jing;McCortney, Kathleen;Steffens, Alicia;Naik, Ulhas;Ahluwalia, Manmeet S.;Bao, Shideng;Horbinski, Craig;Yu, Jennifer S.;Lathia, Justin D.
尽管对胶质母细胞瘤(GBM)进行了治疗，但癌症干细胞(CSCs)会导致复发。CSC抵抗的确切机制，即抑制细胞死亡，目前尚不清楚。我们基于先前的观察，即细胞表面高表达连接黏附分子-A驱动CSC的维持，并确定了下游信号网络，包括半胱氨酸蛋白酶抑制剂SerpinB3。利用基因耗竭的方法，我们发现SerpinB3对于CSC的维持、生存和肿瘤生长以及CSC途径的激活都是必需的。SerpinB3基因的敲除也增加了细胞凋亡和对放射治疗的敏感性。SerpinB3对于缓冲组织蛋白酶L介导的细胞死亡是必不可少的，这种死亡随着辐射的增加而增强。最后，我们发现，在临床前模型中，SerpinB3基因敲除增加了放射的疗效。综上所述，我们的发现确定了GBM CSC特有的生存机制，涉及半胱氨酸蛋白酶抑制剂SerpinB3，并提供了一个潜在的靶点，以提高GBM治疗对治疗耐药的CSCs的疗效。Lauko等人。确定SerpinB3是胶质母细胞瘤肿瘤干细胞中溶酶体介导的细胞死亡的抑制因子。作者证明，SerpinB3抑制溶酶体释放的组织蛋白酶L可导致辐射抵抗。这一轴可能被用于提高胶质母细胞瘤和其他癌症的放射治疗效果。这项研究没有产生新的独特试剂。
Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs. Lauko et al. identify SerpinB3 as an inhibitor of lysosomal-mediated cell death in glioblastoma cancer stem cells. The authors demonstrate that SerpinB3 inhibition of cathepsin L released from lysosomes leads to radiation resistance. This axis may be targeted to improve the efficacy of radiotherapy in glioblastoma and other cancers. This study did not generate new unique reagents.
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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作者：
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