L-Carnitine-Mediated Tumor Cell Protection and Poor Patient Survival Associated with OCTN2 Overexpression in Glioblastoma Multiforme
L-Carnitine-Mediated Tumor Cell Protection and Poor Patient Survival Associated with OCTN2 Overexpression in Glioblastoma Multiforme
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DOI：
10.1158/1078-0432.ccr-18-2380
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发表时间：
2019-05-01
影响因子：
11.5
通讯作者：
Bien-Moeller, Sandra
中科院分区：
文献类型：
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作者：
Fink, Matthias A.;Paland, Heiko;Bien-Moeller, Sandra
目的：细胞凋亡失调、氧化还原适应性机制和对缺氧的抵抗力是胶质母细胞瘤（GBM）对治疗产生耐药性的主要原因。 OCTN2 (SLC22A5) 及其底物左旋肉碱 (LC) 通常被认为是能量代谢的关键因素，越来越多地被认为是细胞保护的参与者。本研究对 GBM 中的 OCTN2/LC 系统进行了全面的表达和生存分析，并阐明了该系统对 GBM 进展的影响。实验设计：在 121 个切除的人类 GBM 标本和 10 个健康脑样本中测量了 OCTN2 表达和 LC 含量，并分析了预后意义。根据 LC 给药，在体外进一步研究了缺氧、代谢和细胞毒性应激对 LN18 GBM 细胞存活和迁移的影响。最后，采用原位小鼠模型研究OCTN2/LC系统对体内GBM生长的抑制作用。结果：与健康脑相比，OCTN2在原发性GBM中表达增加，在复发性GBM中mRNA和蛋白水平更是如此。 OCTN2 高表达与患者总体生存率较差相关；未调整的死亡 HR 为 2.7（95% CI，1.47-4.91；P < 0.001）。对 GBM 细胞施用 LC 会增加其对细胞毒性的耐受性，而 siRNA 介导的 OCTN2 沉默会导致肿瘤细胞活力丧失。与此一致，米曲肼抑制 OCTN2/LC 导致原位 GBM 小鼠模型中肿瘤生长减少。 结论：我们的数据表明 OCTN2/LC 系统在 GBM 进展和治疗耐药中的潜在作用，并表明 OCTN2 作为原发性 GBM 患者的预后标志物。
Purpose: Apoptotic dysregulation, redox adaptive mechanisms, and resilience to hypoxia are major causes of glioblastoma (GBM) resistance to therapy. Commonly known as crucial factors in energy metabolism, OCTN2 (SLC22A5) and its substrate L-carnitine (LC) are increasingly recognized as actors in cytoprotection. This study provides a comprehensive expression and survival analysis of the OCTN2/LC system in GBM and clarifies the system's impact on GBM progression.Experimental Design: OCTN2 expression and LC content were measured in 121 resected human GBM specimens and 10 healthy brain samples and analyzed for prognostic significance. Depending on LC administration, the effects of hypoxic, metabolic, and cytotoxic stress on survival and migration of LN18 GBM cells were further studied in vitro. Finally, an orthotopic mouse model was employed to investigate inhibition of the OCTN2/LC system on in vivo GBM growth.Results: Compared with healthy brain, OCTN2 expression was increased in primary and even more so in recurrent GBM on mRNA and protein level. High OCTN2 expression was associated with a poor overall patient survival; the unadjusted HR for death was 2.7 (95% CI, 1.47-4.91; P < 0.001). LC administration to GBM cells increased their tolerance toward cytotoxicity, whereas siRNA-mediated OCTN2 silencing led to a loss of tumor cell viability. In line herewith, OCTN2/LC inhibition by meldonium resulted in reduced tumor growth in an orthotopic GBM mouse model.Conclusions: Our data indicate a potential role of the OCTN2/LC system in GBM progression and resistance to therapy, and suggests OCTN2 as a prognostic marker in patients with primary GBM.