Fibronectin protects prostate cancer cells from tumor necrosis factor-α-induced apoptosis via the AKT/survivin pathway
Fibronectin protects prostate cancer cells from tumor necrosis factor-α-induced apoptosis via the AKT/survivin pathway
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DOI：
10.1074/jbc.m307627200
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发表时间：
2003-12-12
影响因子：
4.8
通讯作者：
Languino, LR
中科院分区：
文献类型：
--
作者：
Fornaro, M;Plescia, J;Languino, LR
整合素是细胞表面的异二聚体跨膜受体，除了介导细胞与细胞外基质蛋白的黏附外，还调节细胞的存活。这种机制可能被用在癌症中，在癌症中，逃避凋亡总是有助于细胞转化。基质诱导生存信号的分子机制开始被阐明。在此，我们报道了凋亡抑制因子Survivin在体外人前列腺细胞系中的表达，其中在PC3和LNCaP-LN3等侵袭性前列腺癌细胞中表达水平最高，在前列腺癌中表达水平最高。我们还发现，使用Cys(84)-->；Ala显性阴性突变体或Survivin反义cDNA干扰PC3前列腺癌细胞中的Survivin会导致核碎裂、亚二倍体、32 kDa ProForm caspase-3裂解为活性caspase-3，以及caspase底物聚(ADP-核糖)聚合酶的蛋白分解。我们证明，在侵袭性的PC3细胞系中，通过β(1)整合素与纤维连接蛋白的黏附导致Survivin的上调，并保护其免受肿瘤坏死因子-α(TNF-α)诱导的细胞凋亡。相反，在非致瘤的LNCaP细胞系中，Survivin不受细胞黏附的上调。显性阴性的Survivin抵消了纤维连接蛋白保护细胞免受凋亡的能力，而野生型Survivin则保护未贴壁的细胞免受肿瘤坏死因子-α诱导的凋亡。有证据表明，β(1A)整合素的表达是保护转导Survivin的非贴壁细胞免受肿瘤坏死因子-α诱导的凋亡所必需的。相反，含有不同胞浆结构域的β(1C)整合素不能阻止转导Survivin的非贴壁细胞中由肿瘤坏死因子-α诱导的细胞凋亡。最后，我们证明了整合素对Survivin水平的调节是由蛋白激酶B/AKT介导的。这些发现表明，Survivin在前列腺癌细胞中维持一个关键的抗凋亡阈值，并确认整合素信号是对抗死亡受体介导的细胞凋亡的关键生存途径。
Integrins are cell surface heterodimeric transmembrane receptors that, in addition to mediating cell adhesion to extracellular matrix proteins modulate cell survival. This mechanism may be exploited in cancer where evasion from apoptosis invariably contributes to cellular transformation. The molecular mechanisms responsible for matrix-induced survival signals begin to be elucidated. Here we report that the inhibitor of apoptosis survivin is expressed in vitro in human prostate cell lines with the highest levels present in aggressive prostate cancer cells such as PC3 and LNCaP-LN3 as well as in vivo in prostatic adenocarcinoma. We also show that interference with survivin in PC3 prostate cancer cells using a Cys(84)-->Ala dominant negative mutant or survivin antisense cDNA causes nuclear fragmentation, hypodiploidy, cleavage of a 32-kDa proform caspase-3 to active caspase-3, and proteolysis of the caspase substrate poly( ADP-ribose) polymerase. We demonstrate that in the aggressive PC3 cell line, adhesion to fibronectin via beta(1) integrins results in up-regulation of survivin and protection from apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). In contrast, survivin is not up-regulated by cell adhesion in the non-tumorigenic LNCaP cell line. Dominant negative survivin counteracts the ability of fibronectin to protect cells from undergoing apoptosis, whereas wild-type survivin protects non-adherent cells from TNF-alpha-induced apoptosis. Evidence is provided that expression of beta(1A) integrin is necessary to protect non-adherent cells transduced with survivin from TNF-alpha-induced apoptosis. In contrast, the beta(1C) integrin, which contains a variant cytoplasmic domain, is not able to prevent apoptosis induced by TNF-alpha in non-adherent cells transduced with survivin. Finally, we show that regulation of survivin levels by integrins are mediated by protein kinase B/AKT. These findings indicate that survivin is required to maintain a critical anti-apoptotic threshold in prostate cancer cells and identify integrin signaling as a crucial survival pathway against death receptor-mediated apoptosis.