Small molecule-induced mitochondrial disruption directs prostate cancer inhibition via UPR signaling.
Small molecule-induced mitochondrial disruption directs prostate cancer inhibition via UPR signaling.
复制标题
DOI：
10.18632/oncotarget.1130
复制
发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Wolf DA
中科院分区：
文献类型：
--
作者：
Rico-Bautista E;Zhu W;Kitada S;Ganapathy S;Lau E;Krajewski S;Ramirez J;Bush JA;Yuan Z;Wolf DA
我们以前确定SMIP 004（N-（4-丁基-2-甲基-苯基）乙酰胺）作为一种新的人类前列腺癌细胞的癌细胞选择性凋亡诱导剂。SMIP 004降低了细胞周期调节因子的水平，上调了细胞周期蛋白依赖性激酶抑制剂，并导致G1期阻滞，抑制软琼脂中的集落形成和细胞死亡。然而，SMIP 004诱导肿瘤细胞选择性凋亡的机制尚不清楚。在这里，我们使用化学基因组和蛋白质组分析来解开SMIP 004诱导的促凋亡途径，该途径起始于线粒体呼吸的破坏，导致氧化应激。这反过来又激活了两条途径，一条是通过快速靶向细胞周期蛋白D1进行蛋白酶体降解并驱动雄激素受体的转录下调来引发细胞周期停滞，另一条途径是通过未折叠蛋白反应（UPR）下游的MAPK激活来激活促凋亡信号传导。SMIP 004有效抑制小鼠前列腺癌和乳腺癌异种移植物的生长。我们的数据表明，SMIP 004通过诱导线粒体ROS形成，靶向前列腺癌细胞对氧化还原和生物能量失衡的特异性敏感性，可用于癌症治疗。
We previously identified SMIP004 (N-(4-butyl-2-methyl-phenyl) acetamide) as a novel inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. Here, we used chemical genomic and proteomic profiling to unravel a SMIP004-induced pro-apoptotic pathway, which initiates with disruption of mitochondrial respiration leading to oxidative stress. This, in turn, activates two pathways, one eliciting cell cycle arrest by rapidly targeting cyclin D1 for proteasomal degradation and driving the transcriptional downregulation of the androgen receptor, and a second pathway that activates pro-apoptotic signaling through MAPK activation downstream of the unfolded protein response (UPR). SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
DOI：
10.1073/pnas.220247197
发表时间：
2000-11-07
影响因子：
11.1
作者：
Brewer, JW;Diehl, JA
通讯作者：
Diehl, JA