S100A8-targeting siRNA enhances arsenic trioxide-induced myeloid leukemia cell death by down-regulating autophagy
S100A8-targeting siRNA enhances arsenic trioxide-induced myeloid leukemia cell death by down-regulating autophagy
复制标题
靶向 S100A8 的 siRNA 通过下调自噬增强三氧化二砷诱导的骨髓性白血病细胞死亡
DOI：
10.3892/ijmm.2011.806
复制
发表时间：
2012-01-01
影响因子：
5.4
通讯作者：
Cao, Lizhi
中科院分区：
文献类型：
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作者：
Yang, Liangchun;Yang, Minghua;Cao, Lizhi
化疗耐药已成为成功治疗白血病的主要障碍。自噬是细胞成分降解和回收的受调节过程，最近因其在赋予各种常用抗癌疗法耐药性方面的作用而受到越来越多的关注。在此，我们证明 S100 钙结合蛋白家族的成员 S100A8 是自噬过程中化学耐药性的关键调节因子。它与儿童急性髓细胞白血病（AML）的临床状态呈正相关，并且在化疗引起的细胞毒性后从白血病细胞中释放出来。 S100A8表达的敲低增加了白血病细胞对化疗和凋亡的敏感性。此外，通过自噬标记物微管相关蛋白轻链 3 (LC3)-II 的表达增加、SQSTM1/Sequestosome 1 (p62) 的降解和自噬体的形成来评估，抑制 S100A8 表达会减少自噬。此外，增强活性氧（ROS）的刺激促进了S100A8的胞质易位，从而增强了自噬。 S100A8 直接与自噬蛋白 Beclin1 相互作用，取代 Bcl-2。这些结果表明，S100A8 是一种关键的促自噬蛋白，可能通过解离 Beclin1-Bcl-2 复合物来增强细胞存活并调节白血病细胞的化疗耐药性。
Chemoresistance has become a major obstacle to the successful treatment of leukemia. Autophagy, a regulated process of degradation and recycling of cellular constituents, has recently caught increasing attention for its roles in conferring resistance to various commonly used anticancer therapies. Here we showed that the member of the S100 calcium-binding protein family, S100A8, is a critical regulator of chemoresistance in the autophagy process. It positively correlated with the clinical status in childhood acute myeloblastic leukemia (AML) and it was released from leukemia cells after chemotherapy-induced cytotoxicity. Knockdown of S100A8 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis. Moreover, suppressing S100A8 expression decreased autophagy as evaluated by the increased expression of the autophagic marker microtubule-associated protein light chain 3 (LC3)-II, degradation of SQSTM1/Sequestosome 1 (p62) and formation of autophagosomes. Furthermore, stimuli that enhanced reactive oxygen species (ROS) promoted cytosolic translocation of S100A8 and thereby enhanced autophagy. S100A8 directly interacted with the autophagy protein Beclin1 displacing Bcl-2. These results suggest that S100A8 is a critical pro-autophagic protein that enhances cell survival and regulates chemoresistance in leukemia cells likely through disassociating the Beclin1-Bcl-2 complex.