Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer.
Inhibition of STAT3 signaling targets both tumor-initiating and differentiated cell populations in prostate cancer.
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STAT3 信号传导的抑制针对前列腺癌中的肿瘤起始细胞群和分化细胞群
DOI：
10.18632/oncotarget.2314
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发表时间：
2014-09-30
期刊：
影响因子：
--
通讯作者：
Hong Z
中科院分区：
文献类型：
--
作者：
Han Z;Wang X;Ma L;Chen L;Xiao M;Huang L;Cao Y;Bai J;Ma D;Zhou J;Hong Z
尽管对前列腺癌进行了大量的研究，但与疾病进展相关的基因改变和生物学过程仍然部分难以捉摸。在本研究中，我们发现STAT3小分子抑制剂STATTIC在低剂量水平引起S时相聚集，在相对高剂量水平导致前列腺癌细胞大量凋亡。STAT3基因敲除导致肿瘤启动细胞(TICs)和非肿瘤启动细胞(Non-TICS)所依赖的微血管生态位被破坏。原代人前列腺癌细胞和前列腺癌细胞系含有具有干细胞样特征的高醛脱氢酶(ALDHHigh)亚群，其表达活性磷酸化形式的STAT3(PSTAT3)的水平高于非ALDHHigh亚群。即使在低剂量水平下，他汀类药物也能显著减少高ALDH前列腺癌细胞的数量。在前列腺癌细胞系和人前列腺癌来源的细胞中，IL-6都能将非ALDH高表达细胞转化为ALDH高表达细胞，但在STAT3抑制剂存在或STAT3被敲除后，IL-6介导的转化被取消。STAT3基因敲除显著削弱了前列腺癌细胞启动前列腺癌发展的能力。此外，在前列腺癌细胞系异种移植模型和患者源性肿瘤异种移植(PDTX)模型中，阻断STAT3信号通路都能显著有效地消除肿瘤起始细胞和实体瘤细胞群。这一数据表明，通过抑制STAT3来靶向肿瘤起始细胞和分化细胞群体，预计对前列腺癌的治疗具有更好的疗效。
Despite of tremendous research efforts to profile prostate cancer, the genetic alterations and biological processes that correlate with disease progression remain partially elusive. In this study we show that the STAT3 small molecule inhibitor Stattic caused S-phase accumulation at low-dose levels and led to massive apoptosis at a relatively high-dose level in prostate cancer cells. STAT3 knockdown led to the disruption of the microvascular niche which tumor-initiating cells (TICs) and non-tumor initiating cells (non-TICs)depend on. Primary human prostate cancer cells and prostate cancer cell line contained high aldehyde dehydrogenase activity (ALDHhigh) subpopulations with stem cell-like characteristics, which expressed higher levels of the active phosphorylated form of STAT3 (pSTAT3) than that of non-ALDHhigh subpopulations. Stattic could singnificantly decreas the population of ALDHhigh prostate cancer cells even at low-dose levels. IL-6 can convert non-ALDHhigh cells to ALDHhigh cells in prostate cancer cell line as well as from cells derived from human prostate tumors, the conversion mediated by IL-6 was abrogated in the presence of STAT3 inhibitor or upon STAT3 knockdown. STAT3 knockdown significantly impaired the ability of prostate cancer cells to initiate development of prostate adenocarcinoma. Moreover, blockade of STAT3 signaling was significantly effective in eradicating the tumor-initiating and bulk tumor cancer cell populations in both prostate cancer cell-line xenograft model and patient-derived tumor xenograft (PDTX) models. This data suggests that targeting both tumor initiating and differentiated cell populations by STAT3 inhibition is predicted to have greater efficacy for prostate cancer treatment.
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影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
4.7
作者：
Hsieh, I-Shan;Chang, Kung-Chao;Chen, Yuh-Ling
通讯作者：
Chen, Yuh-Ling
影响因子：
50.3
作者：
Lee H;Herrmann A;Deng JH;Kujawski M;Niu G;Li Z;Forman S;Jove R;Pardoll DM;Yu H
通讯作者：
Yu H
影响因子：
--
作者：
Ohanna M;Cheli Y;Bonet C;Bonazzi VF;Allegra M;Giuliano S;Bille K;Bahadoran P;Giacchero D;Lacour JP;Boyle GM;Hayward NF;Bertolotto C;Ballotti R
通讯作者：
Ballotti R
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE