FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway.
FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway.
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DOI：
10.1016/j.canlet.2015.04.017
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发表时间：
2015-07-28
期刊：
影响因子：
9.7
通讯作者：
Amin, A. R. M. Ruhul
中科院分区：
文献类型：
--
作者：
Haque, Abedul;Rahman, Mohammad A.;Fuchs, James R.;Chen, Zhuo Georgia;Khuri, Fadlo R.;Shin, Dong M.;Amin, A. R. M. Ruhul
与化疗药物不同，姜黄素等天然化合物的安全性已经得到了很好的证实。然而，姜黄素的生物利用度低，组织分布有限，生物转化快，体内疗效低，阻碍了姜黄素在癌症中的潜在应用。为了避免这些问题，人们已经合成了更多有效的和生物可用的类似物。在目前的研究中，我们研究了其中一个类似物，FLLL12，在肺癌中的抗肿瘤作用的机制。72小时后用硫代罗丹明B(SRB)测定的IC50值和细胞凋亡分析(Annexin V染色、PARP和caspase-3的裂解)表明，根据细胞系的不同，FLLL12对一组癌前和恶性肺癌细胞株的抑制能力是姜黄素的5-10倍。此外，FLLL12还诱导死亡受体-5(DR5)的表达。用siRNA去除外在凋亡途径的组成部分(DR5、caspase-8和Bid)的表达可以显著保护细胞免受FLLL12诱导的细胞凋亡(p<；0.05)。基因表达分析显示，Fll-12对DR5基因表达无明显影响。有趣的是，抑制全局磷酸酶活性和蛋白酪氨酸磷酸酶(PTPs)，而不是抑制碱性磷酸酶，强烈抑制DR5的表达并显著抑制细胞凋亡(p<；0.05)，表明PTPs参与了DR5表达和细胞凋亡的调节。我们进一步证明，细胞凋亡不依赖于P53和P73。综上所述，我们的结果有力地表明，FLLL12通过激活蛋白酪氨酸磷酸酶(S)而对DR5进行转录后调控，从而诱导肺癌细胞株的凋亡。
Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5–10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase-8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by post-transcriptional regulation of DR5 through activation of protein tyrosine phosphatase(s).
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DOI：
10.1073/pnas.1118244109
发表时间：
2012-03-20
影响因子：
11.1
作者：
Garcia-Perez, Cecilia;Roy, Soumya Sinha;Hajnoczky, Gyoergy
通讯作者：
Hajnoczky, Gyoergy
影响因子：
4.8
作者：
Houghton, Peter;Fang, Rui;Lee, C. C.
通讯作者：
Lee, C. C.
影响因子：
4.5
作者：
Chen, Zhijin;Yu, Dexin;Lu, Zaijun
通讯作者：
Lu, Zaijun
DOI：
10.1073/pnas.0700642104
发表时间：
2007-03-27
影响因子：
11.1
作者：
Amin, A. R. M. Ruhul;Thakur, Vijay S.;Agarwal, Munna L.
通讯作者：
Agarwal, Munna L.
影响因子：
3.7
作者：
Amin, A. R. M. Ruhul;Haque, Abedul;Shin, Dong Moon
通讯作者：
Shin, Dong Moon