Hoa Neil T, Ge Lisheng, Martini Filippo, Chau Vincent, Ahluwalia Amrita, Kruse Carol A, Jadus Martin R
a Research Service HCG, Department Veterans Affairs Medical Center , VA Long Beach Healthcare System , Long Beach , CA , USA.
b Laboratory of Pharmaco-Toxicological Analysis; Department of Pharmacy & Biotechnology (FaBiT) , Alma Mater Studiorum - University of Bologna , Bologna , Italy.
Expert Opin Ther Targets. 2016 Oct;20(10):1155-67. doi: 10.1080/14728222.2016.1208172. Epub 2016 Jul 13.
Temozolomide (TMZ) improves Glioblastoma Multiforme (GBM) patient survival. The invasive behavior of the glioma cells is the cause of GBM relapse. The glioma BK ion channel (gBK) may provide glioma cells with a mechanism to invade surrounding tissue. gBK contains epitopes that cytolytic T lymphocytes (CTLs) can recognize and kill glioma cells. Fascin-1 is an actin crosslinking molecule that supports microvilli; these membrane protrusions provide a physical defense against CTLs. TMZ was investigated to determine its effect on gBK and fascin-1 expression.
Human glioma cells cultured in TMZ were analyzed for their altered mRNA and gBK protein levels by using quantitative real time PCR, immunostaining and cellular functional assays.
TMZ slowed glioma cell growth and inhibited their transmigratory properties due to loss of fascin-1. TMZ induced increased gBK and HLA expression and allowed these TMZ-treated cells to become better targets for gBK-specific CTLs.
Besides its traditional chemotherapeutic effect, TMZ can have four other targeted pathways: 1) slowed glioma cell growth; 2) inhibited glioma cell transmigration; 3) increased HLA-A2 and gBK tumor antigen production; 4) increased CTL-mediated cytolysis of the TMZ treated glioma cells due to the loss of their defensive membrane protrusions supported by fascin-1.
替莫唑胺（TMZ）可提高多形性胶质母细胞瘤（GBM）患者的生存率。胶质瘤细胞的侵袭行为是GBM复发的原因。胶质瘤BK离子通道（gBK）可能为胶质瘤细胞提供一种侵入周围组织的机制。gBK含有细胞毒性T淋巴细胞（CTL）能够识别并杀死胶质瘤细胞的表位。Fascin-1是一种支持微绒毛的肌动蛋白交联分子；这些膜突起为抵御CTL提供了物理防御。对TMZ进行研究以确定其对gBK和Fascin-1表达的影响。
通过定量实时PCR、免疫染色和细胞功能分析，对在TMZ中培养的人胶质瘤细胞的mRNA和gBK蛋白水平变化进行分析。
由于Fascin-1缺失，TMZ减缓了胶质瘤细胞的生长并抑制了其迁移特性。TMZ诱导gBK和HLA表达增加，并使这些经TMZ处理的细胞成为gBK特异性CTL更好的靶标。
除了其传统的化疗作用外，TMZ还可具有其他四种靶向途径：1）减缓胶质瘤细胞生长；2）抑制胶质瘤细胞迁移；3）增加HLA-A2和gBK肿瘤抗原的产生；4）由于经TMZ处理的胶质瘤细胞失去了由Fascin-1支持的防御性膜突起，增加了CTL介导的细胞溶解作用。
