Department of Experimental Medicine and Pathology, Istituto Pasteur Fondazione Cenci Bolognetti, La Sapienza University, Rome, Italy.
Cell Death Dis. 2013 Jul 18;4(7):e730. doi: 10.1038/cddis.2013.263.
Heat-shock protein (HSP) 70 is aberrantly expressed in different malignancies and has a cancer-specific cell-protective effect. As such, it has emerged as a promising target for anticancer therapy. In this study, the effect of the HSP70-specific inhibitor (PES), also Pifitrin-μ, on primary effusion lymphoma (PEL) cell viability was analyzed. PES treatment induced a dose- and time-dependent cytotoxic effect in BC3 and BCBL1 PEL cells by inducing lysosome membrane permeabilization, relocation of cathepsin D in the cytosol, Bid cleavage, mitochondrial depolarization with release and nuclear translocation of apoptosis-activating factor. The PES-induced cell death in PEL cells was characterized by the appearance of Annexin-V/propidium iodide double-positive cells from the early times of treatment, indicating the occurrence of an additional type of cell death other than apoptosis, which, accordingly, was not efficiently prevented by the pan-caspase inhibitor Z-VAD-fmk. Conversely, PES-induced cell death was robustly reduced by pepstatin A, which inhibits Bid and caspase 8 processing. In addition, PES was responsible for a block of the autophagic process in PEL cells. Finally, we found that PES-induced cell death has immunogenic potential being able to induce dendritic cell activation.
热休克蛋白 70（HSP70）在不同的恶性肿瘤中异常表达，具有肿瘤特异性的细胞保护作用。因此，它已成为一种很有前途的抗癌治疗靶点。在这项研究中，分析了 HSP70 特异性抑制剂（PES，也称为 Pifitrin-μ）对原发性渗出性淋巴瘤（PEL）细胞活力的影响。PES 处理通过诱导溶酶体膜通透性、组织蛋白酶 D 在细胞质中的重定位、Bid 切割、线粒体去极化以及凋亡激活因子的核转位，在 BC3 和 BCBL1 PEL 细胞中诱导剂量和时间依赖性细胞毒性作用。PES 诱导的 PEL 细胞死亡的特征是从治疗早期开始出现 Annexin-V/碘化丙啶双阳性细胞，表明除凋亡外还出现了另一种类型的细胞死亡，而这种细胞死亡不能被广谱半胱天冬酶抑制剂 Z-VAD-fmk 有效阻止。相反，PES 诱导的细胞死亡被 Pepstatin A 显著减少，Pepstatin A 抑制 Bid 和 caspase 8 的加工。此外，PES 导致 PEL 细胞的自噬过程受阻。最后，我们发现 PES 诱导的细胞死亡具有免疫原性潜力，能够诱导树突状细胞的激活。
