BAG3 Protein Is Overexpressed in Human Glioblastoma and Is a Potential Target for Therapy
BAG3 Protein Is Overexpressed in Human Glioblastoma and Is a Potential Target for Therapy
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DOI：
10.1016/j.ajpath.2011.02.002
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发表时间：
2011-06-01
影响因子：
6
通讯作者：
Rosati, Alessandra
中科院分区：
文献类型：
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作者：
Festa, Michelina;Del Valle, Luis;Rosati, Alessandra
多形性胶质母细胞瘤占恶性胶质瘤的80%，具有侵袭性和高复发率的特点。尽管治疗取得了进展，但多形性胶质母细胞瘤患者的生存率很差，需要确定新的治疗标志物和分子靶点。最近描述了 BAG3（HSC/HSP70 共伴侣 BAG 家族的成员）在促进体内肿瘤细胞生长中的作用。我们通过 MC 分析了脑肿瘤患者标本中的 BAG3 水平，发现 BAG3 虽然在正常脑组织中呈阴性，但在星形细胞肿瘤中高表达，并且在更具侵袭性的癌症类型中表达越来越多；在胶质母细胞瘤中这一比例尤其高。在大鼠胶质母细胞瘤模型中体外和体内下调 BAG3 会导致对细胞凋亡的敏感性增加，这表明 BAG3 是新疗法的潜在靶点最后，我们确定潜在的分子机制需要形成 BAG3、HSP70 和 BAX 的复合物，以防止 BAX 易位到线粒体，从而保护肿瘤细胞免于凋亡。我们的数据表明 BAG3 是胶质脑肿瘤对治疗敏感性的潜在标志物，因此也是新分子疗法的有吸引力的候选者。 (Am J Pathol 2011, 178:2504-2512; 10.1016/j.ajpath.2011.02.002)
Glioblastoma multiforme, which represents 80% of malignant gliomas, is characterized by aggressiveness and high recurrence rates. Despite therapeutic advances, patients with glioblastoma multiforme show a poor survival, and identification of novel markers and molecular targets for therapy is needed. A role for BAG3, a member of the BAG family of HSC/HSP70 co-chaperones, in promoting tumor cell growth in vivo has recently been described. We analyzed BAG3 levels by MC in specimens from patients affected by brain tumors and we found that BAG3, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive types of cancer; it was particularly high in glioblastomas. Down-regulating BAG3 both in vitro and in vivo in a rat glioblastoma model resulted in increased sensitivity to apoptosis, suggesting that BAG3 is a potential target for novel therapies Finally, we determined that the underlying molecular mechanism requires the formation of a complex of BAG3, HSP70, and BAX that prevents BAX translocation to mitochondria, thus protecting tumor cells from apoptosis. Our data identify BAG3 as a potential marker of g,glial brain tumor sensitivity to therapy and thus also an attractive candidate for new molecular therapies. (Am J Pathol 2011, 178:2504-2512; 10.1016/j.ajpath.2011.02.002)