FGF-2 prevents cancer cells from ER stress-mediated apoptosis via enhancing proteasome-mediated Nck degradation
FGF-2 prevents cancer cells from ER stress-mediated apoptosis via enhancing proteasome-mediated Nck degradation
复制标题
FGF-2 通过增强蛋白酶体介导的 Nck 降解来防止癌细胞免受 ER 应激介导的细胞凋亡
DOI：
10.1042/bj20121671
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发表时间：
2013-05-15
影响因子：
4.1
通讯作者：
Liu, Jianfeng
中科院分区：
文献类型：
--
作者：
Li, Bin;Pi, Zhenjun;Liu, Jianfeng
诱导内质网应激介导的癌细胞凋亡是肿瘤治疗的一种替代方法。成纤维细胞生长因子2诱导的生存信号是否可能与癌细胞中的内质网应激信号相互作用仍不清楚。在本研究中，我们发现，在人肝母细胞瘤HepG2细胞和乳腺癌MCF-7细胞中，经成纤维细胞生长因子-2预处理后，两种不同的内质网应激诱导剂TM(衣霉素)和TG(Thapsigargin)对DNA合成的抑制和对细胞凋亡的诱导作用均减弱。成纤维细胞生长因子-2通过减少内质网应激诱导的CHOP[C/EBP(CCAAT/增强子结合蛋白)同源蛋白]的表达来预防内质网应激诱导的细胞凋亡。本研究进一步证实了成纤维细胞生长因子-2通过ERK1/2(细胞外信号调节蛋白1和2)途径介导TM诱导的CHOP表达减少和细胞凋亡。最后，我们证明了成纤维细胞生长因子-2促进蛋白酶体介导的Nck(酪氨酸激酶非催化区)的降解，Nck是一种含SH(Src同源)2/SH3的接头蛋白。Nck的过表达可抑制成纤维细胞生长因子2诱导的ERK1/2的磷酸化，从而抑制成纤维细胞生长因子2对TM诱导的CHOP表达和细胞凋亡的影响，而Nck表达的降低则阻止了TM诱导的CHOP表达和细胞凋亡。综上所述，本研究的结果首次证明NCK在整合成纤维细胞生长因子-2和内质网应激信号以抵消内质网应激对癌细胞生存的有害影响方面起着关键作用。
Induction of ER (endoplasmic reticulum) stress-mediated apoptosis in cancer cells represents an alternative approach for cancer therapy. Whether FGF-2 (fibroblast growth factor 2)-induced survival signals may interact with ER stress signalling in cancer cells remains elusive. In the present study, we showed that pretreatment with FGF-2 decreased the inhibition of DNA synthesis and induction of apoptosis by two different ER stress inducers, TM (tunicamycin) and TG (thapsigargin), in both human hepatoblastoma HepG2 cells and breast cancer MCF-7 cells. Pretreatment with FGF-2 prevented ER stress-mediated apoptosis by decreasing ER stress-induced CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein] expression. We further demonstrated that pretreatment with FGF-2 mediated the decrease in TM-induced CHOP expression and apoptosis through ERK1/2 (extracellular-signal-regulated kinases 1 and 2) pathway. Finally, we demonstrated that FGF-2 promoted proteasome-mediated degradation of Nck (non-catalytic region of tyrosine kinase adaptor protein), an SH (Src homology) 2/SH3-containing adaptor protein. Whereas overexpression of Nckl decreased FGF-2-induced ERK1/2 phosphorylation to inhibit the effect of FGF-2 on TM-induced CHOP expression and apoptosis, a decrease in Nck expression prevented TM-induced CHOP expression and apoptosis. Taken together, the findings of the present study provide the first evidence that Nck plays a pivotal role in integrating FGF-2 and ER stress signals to counteract the ER stress deleterious effect on cancer cell survival.