Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance
Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance
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DOI：
10.1172/jci39987
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Bourquin, Jean-Pierre
中科院分区：
文献类型：
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作者：
Bonapace, Laura;Bornhauser, Beat C.;Bourquin, Jean-Pierre
对一线化疗（包括糖皮质激素）的体内耐药是急性淋巴细胞白血病（ALL）儿童预后不良的一个强有力的预测因素。调节细胞死亡调节因子代表了一种有吸引力的策略，用于颠覆这种耐药性。在这里，我们报告了多药耐药儿童ALL细胞对糖皮质激素和其他细胞毒性药物的亚细胞毒性浓度的obatoclax（BCL-2家族成员的假定拮抗剂）的完全再敏感。糖皮质激素抵抗的逆转是通过快速激活自噬依赖性坏死性凋亡而发生的，这绕过了线粒体凋亡的阻断。这种效应与自噬诱导剂beclin-1从抗凋亡BCL-2家族成员髓样细胞白血病序列1（MCL-1）中的解离以及哺乳动物雷帕霉素靶蛋白（mTOR）活性的显著降低有关。与mTOR在儿童ALL中糖皮质激素抵抗中的保护作用一致，雷帕霉素与糖皮质激素地塞米松的组合触发了自噬依赖性细胞死亡，具有坏死性凋亡的特征。执行细胞死亡，但不诱导自噬，是严格依赖于受体相互作用蛋白（RIP-I）激酶和圆柱瘤病（头巾肿瘤综合征）（CYLD），两个关键的调节坏死性凋亡的表达。因此，RIP-I的抑制和CYLD的干扰都完全恢复了糖皮质激素抵抗。结合obatoclax体内化疗增敏活性的证据，我们的数据为将这种药理学方法临床转化为难治性ALL患者的治疗提供了令人信服的依据。
In vivo resistance to first-line chemotherapy, including to glucocorticoids, is a strong predictor of poor outcome in children with acute lymphoblastic leukemia (ALL). Modulation,of cell death regulators represents an attractive strategy for subverting such drug resistance. Here we report complete resensitization of multidrug-resistant childhood ALL cells to glucocorticoids and other cytotoxic agents with subcytotoxic concentrations of obatoclax, a putative antagonist of BCL-2 family members. The reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. This effect was associated with dissociation of the autophagy inducer beclin-1 from the antiapoptotic BCL-2 family member myeloid cell leukemia sequence 1 (MCL-1) and with a marked decrease in mammalian target of rapamycin (mTOR) activity. Consistent with a protective role for mTOR in glucocorticoid resistance in childhood ALL, combination of raparnycin with the glucocorticoid dexamethasone triggered autophagy-dependent cell death, with characteristic features of necroptosis. Execution of cell death, but not induction of autophagy, was strictly dependent on expression of receptor-interacting protein (RIP-I) kinase and cylindromatosis (turban tumor syndrome) (CYLD), two key regulators of necroptosis. Accordingly, both inhibition of RIP-I and interference with CYLD restored glucocorticoid resistance completely. Together with evidence for a chemosensitizing activity of obatoclax in vivo, our data provide a compelling rationale for clinical translation of this pharmacological approach into treatments for patients with refractory ALL.