PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling.
PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling.
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DOI：
10.1038/s41419-017-0202-5
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Steigemann P
中科院分区：
文献类型：
--
作者：
Klutzny S;Anurin A;Nicke B;Regan JL;Lange M;Schulze L;Parczyk K;Steigemann P
肿瘤干细胞（Cancer stem cells, CSCs）参与肿瘤转移和耐药发展，从而影响抗癌治疗效果。CSC维持和存活所需的潜在途径尚不完全清楚，仅确定了有限数量的特异性靶向CSC的治疗策略。为了鉴定新的CSC靶向化合物，我们在这里建立了一个基于醛脱氢酶（ALDH）的表型筛选系统，该系统允许对CSC进行自动化和标准化的鉴定。通过对癌细胞进行ALDH活性染色，并应用基于高含量的单细胞群体分析，可以在异质细胞群体中量化具有显著较高ALDH活性（ALDHhigh）的潜在CSC亚群体的比例。我们在体外证实了高ALDH活性是CSC亚群的替代标志物，并证实了Wnt信号是SUM149乳腺癌细胞中CSC维持的重要因素。在小分子筛选中，我们发现磷酸二酯酶5 （PDE5）抑制是多种癌细胞系中靶向CSC维持和存活的潜在策略。通过抑制PDE5消除CSC并不依赖于PKG信号，我们提出了一种新的机制，即PDE5抑制导致cGMP水平升高，从而刺激cAMP/PKA信号通路来消除CSC。
Cancer stem cells (CSCs) are involved in metastasis and resistance development, thus affecting anticancer therapy efficacy. The underlying pathways required for CSC maintenance and survival are not fully understood and only a limited number of treatment strategies to specifically target CSCs have been identified. To identify novel CSC targeting compounds, we here set-up an aldehyde dehydrogenase (ALDH)-based phenotypic screening system that allows for an automated and standardized identification of CSCs. By staining cancer cells for ALDH activity and applying high-content-based single-cell population analysis, the proportion of a potential CSC subpopulation with significantly higher ALDH activity (ALDHhigh) can be quantified in a heterogeneous cell population. We confirmed high ALDH activity as surrogate marker for the CSC subpopulation in vitro and validated Wnt signaling as an essential factor for the maintenance of CSCs in SUM149 breast cancer cells. In a small molecule screen, we identified phosphodiesterase type 5 (PDE5) inhibition as potential strategy to target CSC maintenance and survival in multiple cancer cell lines. CSC elimination by PDE5 inhibition was not dependent on PKG signaling, and we suggest a novel mechanism in which PDE5 inhibition leads to elevated cGMP levels that stimulate cAMP/PKA signaling to eliminate CSCs.
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影响因子：
5.7
作者：
Li N;Xi Y;Tinsley HN;Gurpinar E;Gary BD;Zhu B;Li Y;Chen X;Keeton AB;Abadi AH;Moyer MP;Grizzle WE;Chang WC;Clapper ML;Piazza GA
通讯作者：
Piazza GA
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
13.5
作者：
Das, Anindita;Durrant, David;Salloum, Fadi N.;Xi, Lei;Kukreja, Rakesh C.
通讯作者：
Kukreja, Rakesh C.
影响因子：
2.9
作者：
Kim RJ;Nam JS
通讯作者：
Nam JS