Subramanian Chitra, Jarzembowski Jason A, Halsey Sonja M, Kuick Rork, Opipari Anthony W, Castle Valerie P, Kwok Roland P S
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Tumour Biol. 2011 Apr;32(2):285-94. doi: 10.1007/s13277-010-0120-y. Epub 2010 Nov 2.
Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.
簇集素是一种广泛表达的糖蛋白，有多个结合伴侣，包括白细胞介素-6、Ku70和Bax。簇集素通过与活化的Bax结合并将其隔离在细胞质中，从而阻止Bax进入线粒体、释放细胞色素c并触发凋亡，进而阻断凋亡。由于簇集素表达增加与肿瘤的侵袭性行为相关，抑制簇集素可能对癌症治疗有益。我们最近的研究结果表明，在神经母细胞瘤细胞中，细胞质中的Bax也与Ku70结合；当Ku70被乙酰化时，Bax被释放并可引发细胞死亡。因此，通过使用组蛋白脱乙酰酶抑制剂等方法增加Ku70的乙酰化，可能在促进神经母细胞瘤肿瘤细胞死亡方面具有治疗作用。由于簇集素、Bax和Ku70形成一个复合物，似乎簇集素可能通过抑制Ku70乙酰化和阻止Bax释放来介导其抗凋亡作用。然而，我们的结果表明，虽然簇集素水平确实决定了神经母细胞瘤细胞对组蛋白脱乙酰酶抑制剂诱导的细胞死亡的敏感性，但它是在不影响组蛋白脱乙酰酶抑制剂诱导的Ku70乙酰化的情况下做到这一点的。我们的结果表明，在神经母细胞瘤中，簇集素在Ku70乙酰化的下游发挥其抗凋亡作用，可能是通过直接阻断Bax的激活来实现的。
