Cheriyan Vino T, Wang Ying, Muthu Magesh, Jamal Shazia, Chen Di, Yang Huanjie, Polin Lisa A, Tarca Adi L, Pass Harvey I, Dou Q Ping, Sharma Sunita, Wali Anil, Rishi Arun K
Department of Oncology, Wayne State University, Detroit, Michigan, United States of America; John D. Dingell VA Medical Center, Detroit, Michigan, United States of America.
Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Wayne State University, Detroit, Michigan, United States of America.
PLoS One. 2014 Apr 1;9(4):e93711. doi: 10.1371/journal.pone.0093711. eCollection 2014.
Dithiocarbamate compound Disulfiram (DSF) that binds with copper and functions as an inhibitor of aldehyde dehydrogenase is a Food and Drug Administration approved agent for treatment of alcoholism. Copper complexed DSF (DSF-Cu) also possesses anti-tumor and chemosensitizing properties; however, its molecular mechanisms of action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF-Cu and the molecular mechanisms involved. DSF-Cu inhibited growth of the murine as well as human MPM cells in part by increasing levels of ubiquitinated proteins. DSF-Cu exposure stimulated apoptosis in MPM cells that involved activation of stress-activated protein kinases (SAPKs) p38 and JNK1/2, caspase-3, and cleavage of poly-(ADP-ribose)-polymerase, as well as increased expression of sulfatase 1 and apoptosis transducing CARP-1/CCAR1 protein. Gene-array based analyses revealed that DSF-Cu suppressed cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF inhibited MPM cell growth and survival by upregulating cell cycle inhibitor p27Kip1, IGFBP7, and inhibitors of NF-κB such as ABIN 1 and 2 and Inhibitory κB (IκB)α and β proteins. DSF-Cu promoted cleavage of vimentin, as well as serine-phosphorylation and lysine-63 linked ubiquitination of podoplanin. Administration of 50 mg/kg DSF-Cu by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo. Although podoplanin expression often correlates with metastatic disease and poor prognosis, phosphorylation of serines in cytoplasmic domain of podoplanin has recently been shown to interfere with cellular motility and migration signaling. Post-translational modification of podoplanin and cleavage of vimentin by DSF-Cu underscore a metastasis inhibitory property of this agent and together with our in vivo studies underscore its potential as an anti-MPM agent.
与铜结合并作为乙醛脱氢酶抑制剂发挥作用的二硫代氨基甲酸盐化合物双硫仑（DSF）是一种经美国食品药品监督管理局批准用于治疗酒精中毒的药物。铜络合的DSF（DSF-Cu）也具有抗肿瘤和化学增敏特性；然而，其作用的分子机制仍不清楚。在此，我们研究了DSF-Cu对恶性胸膜间皮瘤（MPM）的抑制作用及其相关分子机制。DSF-Cu部分通过增加泛素化蛋白水平来抑制小鼠和人MPM细胞的生长。DSF-Cu处理刺激了MPM细胞的凋亡，这涉及应激激活蛋白激酶（SAPKs）p38和JNK1/2、半胱天冬酶-3的激活以及聚（ADP-核糖）聚合酶的切割，以及硫酸酯酶1表达的增加和凋亡转导蛋白CARP-1/CCAR1的表达。基于基因阵列的分析表明，DSF-Cu抑制了包括基质金属肽酶3和10在内的细胞生长和促进转移的基因。DSF通过上调细胞周期抑制剂p27Kip1、IGFBP7以及NF-κB抑制剂如ABIN 1和2以及抑制性κB（IκB）α和β蛋白来抑制MPM细胞的生长和存活。DSF-Cu促进波形蛋白的切割，以及血小板反应蛋白的丝氨酸磷酸化和赖氨酸-63连接的泛素化。每天腹腔注射50 mg/kg DSF-Cu可抑制小鼠MPM细胞衍生肿瘤在体内的生长。尽管血小板反应蛋白的表达通常与转移性疾病和不良预后相关，但最近已表明血小板反应蛋白胞质结构域中丝氨酸的磷酸化会干扰细胞运动和迁移信号。DSF-Cu对血小板反应蛋白的翻译后修饰和波形蛋白的切割突出了该药物的转移抑制特性，并且与我们的体内研究一起突出了其作为抗MPM药物的潜力。
