Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist.
Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist.
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DOI：
10.1371/journal.pone.0013831
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发表时间：
2010-11-03
期刊：
影响因子：
3.7
通讯作者：
Jothy S
中科院分区：
文献类型：
--
作者：
Prud'homme GJ;Glinka Y;Toulina A;Ace O;Subramaniam V;Jothy S
癌症干细胞（CSC）对癌症化疗的抗性增加。它们可以通过与化疗药物一起生长和/或通过分选表达CSC标志物如醛脱氢酶-I（ALDH）的细胞而富集为药物存活的CSC（D-CSC）。CSC在琼脂中形成集落，在低粘附培养物中形成乳腺球，并在Scid小鼠中异种移植后形成肿瘤。我们假设曲尼司特是一种具有抗癌活性的无毒口服活性药物，可以抑制乳腺CSC。我们检查了乳腺癌细胞系或通过这些细胞与米托蒽醌的生长产生的D-CSC。曲尼司特抑制集落形成、乳腺球形成和干细胞标志物表达。米托蒽醌选择的细胞富集表达干细胞标志物ALDH、c-kit、Oct-4和ABCG 2的CSC，并有效形成乳腺球。曲尼司特显著抑制D-CSC的乳腺球形成，并在高相关浓度下解离形成的乳腺球。它对HER-2+和三阴性细胞系的D-CSC都有效。曲尼司特在体内也是有效的，因为它可以预防静脉注射三阴性（MDA-MB-231）米托蒽醌选择细胞的小鼠的肺转移。曲尼司特在癌症中的分子靶点尚不清楚，但在这里我们证明了它是一种芳烃受体（AHR）激动剂，这起着关键作用。AHR是一种转录因子，可被2，3，7，8-四氯二苯并对二恶英（TCDD）、多环芳烃等配体激活。曲尼司特诱导AHR易位至细胞核并刺激CYP 1A 1表达（AHR活化的标志物）。它抑制AHR与CDK 4的结合，这与细胞周期停滞有关。D-CSC表达的AHR水平高于其他细胞。用siRNA敲低AHR或用AHR拮抗剂阻断，完全消除了曲尼司特的抗增殖和抗乳腺球活性。因此，曲尼司特的抗癌作用是AHR依赖性的。我们发现曲尼司特是一种AHR激动剂，对乳腺CSC具有抑制作用。它对选择用于抗癌药物抗性的三阴性乳腺癌细胞的CSC有效。这些结果表明，它可能会在乳腺癌的治疗中找到应用。
Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug-surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs. We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative (MDA-MB-231) mitoxantrone-selected cells. The molecular targets of tranilast in cancer have been unknown, but here we demonstrate it is an aryl hydrocarbon receptor (AHR) agonist and this plays a key role. AHR is a transcription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. Tranilast induced translocation of the AHR to the nucleus and stimulated CYP1A1 expression (a marker of AHR activation). It inhibited binding of the AHR to CDK4, which has been linked to cell-cycle arrest. D-CSCs expressed higher levels of the AHR than other cells. Knockdown of the AHR with siRNA, or blockade with an AHR antagonist, entirely abrogated the anti-proliferative and anti-mammosphere activity of tranilast. Thus, the anti-cancer effects of tranilast are AHR dependent. We show that tranilast is an AHR agonist with inhibitory effects on breast CSCs. It is effective against CSCs of triple-negative breast cancer cells selected for anti-cancer drug resistance. These results suggest it might find applications in the treatment of breast cancer.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
7.4
作者：
Fillmore, Christine M.;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
2.5
作者：
Dean, Michael
通讯作者：
Dean, Michael
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：
3
作者：
Bencko, V.;Rames, J.;Trnovec, T.
通讯作者：
Trnovec, T.