Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma
Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma
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DOI：
10.1182/blood-2002-07-2130
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发表时间：
2003-02-15
期刊：
影响因子：
20.3
通讯作者：
Tosato, G
中科院分区：
文献类型：
--
作者：
Aoki, Y;Feldman, GM;Tosato, G
尽管在分子发病机制方面有一些令人兴奋的新线索，但艾滋病定义的原发性渗出性淋巴瘤（PEL）仍然是一种致命的恶性肿瘤。在PEL的管理缺乏实质性进展，需要创新的治疗方法。靶向对细胞存活至关重要的细胞内分子是治疗PEL的一种未探索的策略。在这里，我们表明，信号转导和转录激活因子-3（STAT 3）的抑制导致细胞凋亡的PEL细胞。STAT 3在PEL细胞系BC-1、BCBL-1和VG-1中组成型磷酸化。显性负性STAT 3的转导和药理学STAT 3抑制引起半胱天冬酶依赖性细胞死亡。尽管已知STAT 3激活诱导Bcl-2家族蛋白的表达，但PEL细胞凋亡不依赖于Bcl-2、BCI-X-L或Mcl-1蛋白表达。相反，STAT 3的抑制诱导转录抑制生存素，最近确定的细胞凋亡抑制剂。Survivin的强制过表达可使VG-1细胞免于STAT 3抑制诱导的凋亡。我们的研究结果表明，激活的STAT 3信号直接有助于通过阻止凋亡，通过促生存蛋白生存素的恶性进展的PEL。由于组成型STAT 3激活和生存素表达已被广泛记录在不同类型的癌症中，它们的联系可能延伸到许多恶性肿瘤，并对其发病机制至关重要。(C)2003年，美国血液学会。
Despite some exciting new leads in molecular pathogenesis, AIDS-defining primary effusion lymphoma (PEL) remains a fatal malignancy. The lack of substantial progress in the management of PEL demands innovative treatment approaches. Targeting intracellular molecules critical to cell survival is one unexplored strategy for treating PEL. Here we show that inhibition of signal transducer and activator of transcription-3 (STAT3) leads to apoptosis in PEL cells. STAT3 is constitutively phosphorylated in PEL cell lines BC-1, BCBL-1, and VG-1. Transduction of dominant-negative STAT3 and pharmacological STAT3 inhibition caused caspase-dependent cell death. Although STAT3 activation is known to induce expression of Bcl-2 family proteins, PEL cell apoptosis was independent of Bcl-2, BCI-X-L, or Mcl-1 protein expression. Instead, STAT3 inhibition induced transcriptional repression of survivin, a recently identified inhibitor of apoptosis. Forced overexpression of survivin rescued VG-1 cells from apoptosis induced by STAT3 inhibition. Our findings suggest that activated STAT3 signaling directly contributes to malignant progression of PEL by preventing apoptosis, acting through the prosurvival protein survivin. Since constitutive STAT3 activation and survivin expression have been widely documented in different types of cancers, their linkage may extend to many malignancies and be critical to their pathogenesis. (C) 2003 by The American Society of Hematology.