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首页> 外文期刊>Lung cancer: Journal of the International Association for the Study of Lung Cancer >Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis.
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Down-regulation of HSP27 sensitizes TRAIL-resistant tumor cell to TRAIL-induced apoptosis.

机译：HSP27的下调使TRAIL耐药肿瘤细胞对TRAIL诱导的细胞凋亡敏感。

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摘要

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) has recently emerged as a cancer therapeutic agent because it preferentially induces apoptosis in human cancer over normal cells. Most tumor cells, including lung cancer cell line A549, unfortunately, are resistant to TRAIL treatment even at high dose. Recent studies indicated that TRAIL-resistant cancer cells could be sensitized to TRAIL by combination therapy. Stress and heat shock proteins such as HSP90, HSP70 and HSP27 are induced in response to a wide variety of physiological environmental insults including heat, reactive oxygen species or anticancer drugs. Their elevated expressions facilitate cells to survive in stress circumstances. The HSP27 expression is enhanced in many tumor cells, implying that it is involved in tumor progression and the development of treatment resistance in various tumors, including lung cancer. This fact suggests a novel strategy for the treatment of cancer via inhibiting the function of HSP27. In this study, we investigated the inhibitory effect of a small interfering (si) RNA on the expression of HSP27 gene in the TRAIL-resistant human lung adenocarcinoma cell line A549, and the effect of HSP27 siRNA on drug sensitization of A549 cells to TRAIL treatment. The results showed that treatment of A549 cells with HSP27 siRNA down-regulated HSP27 expression but did not induce significant apoptosis. However, combination of HSP27 siRNA with TRAIL-induced significant apoptosis in TRAIL-resistant A549 cells. In addition to inducing caspases activation and apoptosis, combined treatment with HSP27 siRNA and TRAIL also increased JNK and p53 expression and activity. Collectively, these findings provide a conclusion that siRNA targeting of the HSP27 gene specifically down-regulated HSP27 expression in A549 cells, and sensitized the cells to TRAIL-induced apoptosis.
机译：肿瘤坏死因子-α相关的凋亡诱导配体（TRAIL）最近已成为一种癌症治疗剂，因为它比正常细胞优先诱导人癌的凋亡。不幸的是，大多数肿瘤细胞，包括肺癌细胞系A549，即使在高剂量下也对TRAIL治疗有抗性。最近的研究表明，通过联合治疗可使TRAIL耐药的癌细胞对TRAIL敏感。应激和热休克蛋白（例如HSP90，HSP70和HSP27）是对多种生理环境损伤（包括热，活性氧或抗癌药）的反应而诱导的。它们的高表达促进细胞在压力条件下存活。 HSP27的表达在许多肿瘤细胞中均得到增强，这意味着它参与了多种肿瘤（包括肺癌）的肿瘤进展和抗药性的发展。这一事实表明通过抑制HSP27的功能来治疗癌症的新策略。在这项研究中，我们研究了小干扰（si）RNA对TRAIL耐药的人肺腺癌细胞A549中HSP27基因表达的抑制作用，以及HSP27 siRNA对A549细胞对TRAIL治疗的药物敏感性的影响。结果显示，用HSP27 siRNA处理A549细胞可下调HSP27表达，但不会诱导明显的细胞凋亡。但是，HSP27 siRNA与TRAIL诱导的TRAIL耐药A549细胞显着凋亡。除了诱导胱天蛋白酶激活和凋亡外，与HSP27 siRNA和TRAIL联合治疗还提高了JNK和p53的表达和活性。总的来说，这些发现提供了一个结论，即靶向HSP27基因的siRNA特异性下调了A549细胞中HSP27的表达，并使细胞对TRAIL诱导的细胞凋亡敏感。

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