Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1
Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1
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DOI：
10.1182/blood-2012-02-407999
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发表时间：
2012-07-26
期刊：
影响因子：
20.3
通讯作者：
Starczynowski, Daniel T.
中科院分区：
文献类型：
--
作者：
Fang, Jing;Rhyasen, Garrett;Starczynowski, Daniel T.
硼替佐米（万珂）广泛用于治疗各种人类癌症;然而，其作用机制尚未完全了解，特别是在骨髓恶性肿瘤中。硼替佐米是一种选择性和可逆的蛋白酶体抑制剂。奇怪的是，我们发现硼替佐米诱导TRAF 6蛋白的蛋白酶体非依赖性降解，而不是mRNA，在骨髓增生异常综合征（MDS）和急性髓性白血病（AML）细胞系和原代细胞。TRAF 6蛋白的减少与硼替佐米诱导的自噬一致，随后与MDS/AML细胞中的凋亡一致。RNAi介导的TRAF 6敲低致敏硼替佐米敏感和耐药细胞系，强调了TRAF 6在硼替佐米诱导的细胞毒性中的重要性。表达靶向TRAF 6的shRNA的硼替佐米耐药细胞由于蛋白酶体亚基α-1（PSMA 1）的下调而对硼替佐米的细胞毒性作用重新敏感。为了确定TRAF 6在MDS/AML细胞中丢失的分子后果，在本研究中，我们应用基因表达谱并鉴定了凋亡基因签名。TRAF 6在MDS/AML细胞系或患者样本中的敲低导致快速凋亡和恶性造血干/祖细胞功能受损。总之，我们在此描述了TRAF 6通过硼替佐米/自噬介导的降解调节的新机制，以及TRAF 6通过控制PSMA 1表达改变MDS/AML对硼替佐米的敏感性的新机制。（血。2012;120（4）：858-867）
Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit alpha-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression. (Blood. 2012;120(4):858-867)