Zinc chelation: a metallothionein 2A's mechanism of action involved in osteosarcoma cell death and chemotherapy resistance.
Zinc chelation: a metallothionein 2A's mechanism of action involved in osteosarcoma cell death and chemotherapy resistance.
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DOI：
10.1038/cddis.2013.405
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发表时间：
2013-10-24
影响因子：
9
通讯作者：
Fromigue, O.
中科院分区：
文献类型：
--
作者：
Habel, N.;Hamidouche, Z.;Girault, I.;Patino-Garcia, A.;Lecanda, F.;Marie, P. J.;Fromigue, O.
骨肉瘤是儿童和青少年中最常见的原发性骨肿瘤。对化疗的组织学反应是与生存相关的关键临床因素。我们之前的研究表明，他汀类药物在体外具有抗肿瘤作用，诱导凋亡细胞死亡，降低细胞迁移和侵袭能力，并与标准药物联合使用时增强细胞毒性作用。对照和他汀处理细胞的转录组比较分析显示，包括金属硫蛋白（MT） 2A在内的几个基因表达强烈。慢病毒转导的MT2A过表达降低了生物可利用锌水平，这与骨肉瘤细胞活力降低和细胞分化增强有关。相比之下，MT2A沉默不改变细胞活力，但强烈抑制成骨细胞标志物的表达和分化过程。MT2A过表达通过直接螯合含铂药物和间接作用于p53锌依赖活性诱导对细胞毒药物的化疗耐药。相反，取消MT2A会增强化疗药物对骨肉瘤细胞的细胞毒性作用。最后，来自化疗活检的临床样本显示，表达低MT2A水平的肿瘤细胞预后良好（反应良好的患者生存率较长），而高MT2A水平的肿瘤细胞预后不良（反应较差的患者）。综上所述，这些数据表明MT2A有助于骨肉瘤的化疗耐药，锌螯合部分介导了这种作用。数据还表明，MT2A可能是骨肉瘤化疗敏感性的潜在新预后标志物。
Osteosarcoma is the most common primary tumor of bone occurring in children and adolescents. The histological response to chemotherapy represents a key clinical factor related to survival. We previously showed that statins exhibit antitumor effects in vitro, inducing apoptotic cell death, reducing cell migration and invasion capacities and strengthening cytotoxic effects in combination with standard drugs. Comparative transcriptomic analysis between control and statin-treated cells revealed strong expression of several genes, including metallothionein (MT) 2A. MT2A overexpression by lentiviral transduction reduced bioavailable zinc levels, an effect associated with reduced osteosarcoma cell viability and enhanced cell differentiation. In contrast, MT2A silencing did not modify cell viability but strongly inhibited expression of osteoblastic markers and differentiation process. MT2A overexpression induced chemoresistance to cytotoxic drugs through direct chelation of platinum-containing drugs and indirect action on p53 zinc-dependent activity. In contrast, abrogation of MT2A enhanced cytotoxic action of chemotherapeutic drugs on osteosarcoma cells. Finally, clinical samples derived from chemonaive biopsies revealed that tumor cells expressing low MT2A levels correspond to good prognostic (good responder patients with longer survival rate), whereas high MT2A levels were associated with adverse prognosis (poor responder patients). Taken together, these data show that MT2A contributes to chemotherapy resistance in osteosarcoma, an effect partially mediated by zinc chelation. The data also suggest that MT2A may be a potential new prognostic marker for osteosarcoma sensitivity to chemotherapy.
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影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1016/j.jtemb.2005.06.003
发表时间：
2005-01-01
影响因子：
3.5
作者：
Ghayour-Mobarhan, M;Lamb, DJ;Ferns, GAA
通讯作者：
Ferns, GAA
影响因子：
2.9
作者：
Leonhardt, W;Kurktschiev, T;Hanefeld, M
通讯作者：
Hanefeld, M
影响因子：
3.9
作者：
Dohi, Y;Shimaoka, H;Minami, T
通讯作者：
Minami, T
DOI：
10.1073/pnas.95.7.3483
发表时间：
1998-03-31
影响因子：
11.1
作者：
Jiang, LJ;Maret, W;Vallee, BL
通讯作者：
Vallee, BL