MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.
MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.
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DOI：
10.1158/1078-0432.ccr-10-1820
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发表时间：
2011-07-01
期刊：
影响因子：
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通讯作者：
Cho HJ
中科院分区：
文献类型：
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作者：
Nardiello T;Jungbluth AA;Mei A;Diliberto M;Huang X;Dabrowski A;Andrade VC;Wasserstrum R;Ely S;Niesvizky R;Pearse R;Coleman M;Jayabalan DS;Bhardwaj N;Old LJ;Chen-Kiang S;Cho HJ
I型黑色素瘤抗原基因(MAGE)在癌症中普遍表达，这加剧了人们对它们可能是具有致癌潜力的治疗靶点的猜测。它们与具有E3泛素连接酶活性的环状结构域蛋白形成复合体，促进P53的降解。在多发性骨髓瘤患者的肿瘤标本中检测到MAGE-A3，其表达与Ki-67+恶性细胞的高比例相关。在这份报告中，我们研究了MAGE-A在促进增殖性多发性骨髓瘤细胞存活方面的机制作用。通过免疫组织化学分析，将一组独立的肿瘤标本分成两组：新诊断、未治疗的患者和化疗后复发的患者，研究MAGE-A3的表达对体内生存和增殖的影响。通过shRNA干扰抑制MAGE-A3在骨髓瘤细胞系和原代细胞中的表达，并评价其对细胞增殖和凋亡的影响，以探讨MAGE-A3的体外活性机制。与新诊断的患者相比，在复发患者中检测到MAGE-A3的比例显著更高，建立了与疾病进展的新相关性。MAGE-A的沉默表明，MAGE-A对细胞周期是必需的，但对增殖的骨髓瘤细胞的生存是必需的。MAGE-A的缺失通过P53依赖激活促凋亡的Bax表达和通过P53依赖和独立机制降低Survivin的表达而导致细胞凋亡。这些数据支持MAGE-A通过两种新的机制抑制增殖中的骨髓瘤细胞的凋亡，从而在多发性骨髓瘤的发生和发展中发挥作用。
The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67+ malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells. The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups; newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by shRNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis. MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared to newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A demonstrated that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of pro-apoptotic Bax expression and by reduction of survivin expression through both p53-dependent and independent mechanisms. These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.