RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells
RACK1 deficiency synergizes with all-trans retinoic acid to induce apoptosis in human acute promyelocytic leukemia cells
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RACK1缺陷与全反式视黄酸协同诱导人急性早幼粒细胞白血病细胞凋亡
DOI：
10.1007/s11010-018-3402-0
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发表时间：
2018-07
影响因子：
4.3
通讯作者：
Wang Jing
中科院分区：
文献类型：
--
作者：
Wu Huifang;Liu Jian;Huang Xiaofeng;Pian Lili;Cheng Qianqian;Wang Qingyang;Zhao Min;Lin Zhou;Shen Beifen;Zhang Jiyan;Li Shulian;Wang Jing
全反式维甲酸（ATRA）作为一种经典的诱导分化剂，已广泛应用于急性早幼粒细胞白血病（APL）的治疗。但是，由于ATRA会引起外周血白细胞的蓄积，其严重的毒副作用使其临床应用受到严格的限制。支架蛋白RACK 1（活化C激酶1受体）调节多种信号通路，已被提出有助于白血病祖细胞的存活。但目前尚不清楚它是否也参与了APL的致癌生长。在本研究中，我们证明内源性RACK 1表达的沉默与ATRA协同促进NB 4和HL-60 APL细胞的死亡，而不影响ATRA诱导的细胞分化。有趣的是，RACK 1敲低联合ATRA治疗主要诱导细胞凋亡。这与艾达鲁肽与ATRA联合诱导的坏死细胞死亡不同，ATRA是临床上广泛使用的预防中性粒细胞蓄积的方案。进一步的研究表明，溶酶体-自噬途径可能是RACK 1抗凋亡作用的原因。综上所述，我们的研究结果表明，RACK 1是必不可少的，在维持APL的恶性特征，并针对RACK 1可能有希望的治疗APL的治疗意义。
As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome–autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.
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