Storniolo Antonello, Raciti Marisa, Cucina Alessandra, Bizzarri Mariano, Di Renzo Livia
Department of Experimental Medicine, Sapienza University, Viale Regina Elena 324, 00161 Rome, Italy.
Department of Surgery P. Valdoni, Sapienza University, Via A. Scarpa 14, 00161 Rome, Italy.
Oxid Med Cell Longev. 2015;2015:645157. doi: 10.1155/2015/645157. Epub 2015 Apr 2.
Relative to their normal counterparts, tumor cells generally exhibit a greater "stress phenotype" and express heat shock proteins (Hsp) that represent candidate targets for anticancer therapy. Here we investigated the role of Hsp70 in survival induced by endoplasmic reticulum (ER) stressors in human leukemia U937 cells. Quercetin, a major dietary flavonoid, or specific silencing affected the expression level of Hsp70 and did not allow the upregulation of inositol-requiring kinase 1α (IRE1α), the prototype ER stress sensor regulating the unfolded protein response (UPR), that protects the cells against the stress of misfolded proteins in the ER. The reduction of Hsp70 prevented the upregulation of immunoglobulin heavy-chain binding protein (BiP), but not of CCAAT/enhancer-binding protein-homologous protein (CHOP), and induced apoptosis. Also specific silencing of IRE1α or inhibition of its endoribonuclease activity by 4μ8c hampered the upregulation of BiP, but not of CHOP, and induced apoptosis. These results suggest that drugs affecting the Hsp70-IRE1α axis, like quercetin, or affecting directly IRE1α may represent an effective adjuvant antileukemia therapy.
相对于正常细胞，肿瘤细胞通常表现出更强的“应激表型”，并表达热休克蛋白（Hsp），这些蛋白是抗癌治疗的潜在靶点。在此，我们研究了Hsp70在人白血病U937细胞内质网（ER）应激诱导的细胞存活中的作用。主要膳食类黄酮槲皮素或特异性沉默影响了Hsp70的表达水平，且不允许肌醇需求激酶1α（IRE1α）上调，IRE1α是调节未折叠蛋白反应（UPR）的内质网应激传感器原型，可保护细胞免受内质网中错误折叠蛋白的应激。Hsp70的减少阻止了免疫球蛋白重链结合蛋白（BiP）的上调，但不影响CCAAT/增强子结合蛋白同源蛋白（CHOP）的上调，并诱导细胞凋亡。IRE1α的特异性沉默或4μ8c对其核糖核酸内切酶活性的抑制也阻碍了BiP的上调，但不影响CHOP的上调，并诱导细胞凋亡。这些结果表明，影响Hsp70-IRE1α轴的药物，如槲皮素，或直接影响IRE1α的药物可能是一种有效的辅助抗白血病治疗方法。
