Low molecular weight heparin ablates lung cancer cisplatin-resistance by inducing proteasome-mediated ABCG2 protein degradation.
Low molecular weight heparin ablates lung cancer cisplatin-resistance by inducing proteasome-mediated ABCG2 protein degradation.
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DOI：
10.1371/journal.pone.0041035
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Zheng K
中科院分区：
文献类型：
--
作者：
Niu Q;Wang W;Li Y;Ruden DM;Wang F;Li Y;Wang F;Song J;Zheng K
癌旁群（SP）细胞通常被称为癌症干细胞，被认为是肺癌化疗耐药性的原因，目前还没有药物可以专门针对这些细胞。我们假设低分子量肝素 (LMWH) 可能会影响 SP 细胞的生物学特性，并可用于临床靶向这些细胞。为了测试这一点，通过流式细胞术分选从顺铂 (DDP) 耐药的肺腺癌 A549/DDP 细胞中分离出 SP 细胞。与非SP细胞相比，SP细胞在体外形成的集落数量增加，体内致瘤性增加1000倍。增殖和凋亡测定表明LMWH对肺SP细胞增殖或凋亡没有显着影响。然而，通过 FACS 和蛋白质印迹分析，LMWH 降低了肺 SP 细胞集落形成能力和多药转运蛋白 ABCG2 的蛋白表达，但 RT-PCR 不影响其 mRNA 水平。一致地，与对照组相比，LMWH 处理的肿瘤组织中 ABCG2 的免疫组织化学染色显着减少。此外，我们发现蛋白酶体抑制剂 MG132（而非溶酶体抑制剂亮肽素和胃酶抑素 A）可以恢复 LMWH 处理的 SP 细胞中的 ABCG2 蛋白水平。这些表明 LMWH 通过蛋白酶体介导的 ABCG2 蛋白水平降低来消除肺 SP 细胞的化疗耐药性，而不影响其 mRNA 水平。我们还确定 LMWH 与顺铂联合可以克服顺铂耐药性并在体外和体内诱导肺 SP 细胞凋亡。这项研究为结合使用针对肺 SP 细胞的 LMWH 与化疗来提高肺癌生存率提供了实验基础。
Cancer side population (SP) cells, which are often referred to as cancer stem cells, are thought to be responsible for lung cancer chemotherapy resistance, and currently no drug can specifically target these cells. We hypothesize low-molecular-weight heparin (LMWH) may affect the biological properties of SP cells and could be used to clinically target these cells. To test this, SP cells were isolated from cisplatin (DDP)-resistant lung adenocarcinoma A549/DDP cells by flow cytometric sorting. Compared to non-SP cells, SP cells formed increased numbers of colonies in vitro, and had a 1000-fold increase in tumorigenicity in vivo. Proliferation and apoptosis assays demonstrated LMWH had no significant effect on lung SP cell proliferation or apoptosis. However, LMWH reduced lung SP cell colony formation ability and protein expression of the multidrug transporter, ABCG2, by FACS and western blot analyses without affecting its mRNA levels by RT-PCR. Consistently, immunohistochemistry stainings of ABCG2 in LMWH-treated tumor tissues were significantly reduced compared with those in controls. Further, we found proteasomal inhibitor MG132, but not lysosomal inhibitors leupeptin and pepstatin A, could restore ABCG2 protein levels in LMWH-treated SP cells. These suggest LMWH ablates lung SP cell chemoresistance by proteasome-mediated reduction of ABCG2 protein levels without affecting its mRNA levels. We also determined LMWH combined with cisplatin could overcome cisplatin-resistance and induced lung SP cells apoptosis both in vitro and in vivo. This study provides an experimental basis for using a combination of LMWH, which targets lung SP cells, with chemotherapy to improve lung cancer survival.
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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：
11.3
作者：
Akl, Elie A.;van Doormaal, Frederiek F.;Schuenemann, Holger J.
通讯作者：
Schuenemann, Holger J.
影响因子：
10.4
作者：
Altinbas, M;Coskun, HS;Soyuer, S
通讯作者：
Soyuer, S
影响因子：
8.5
作者：
Chatzinikolaou, G.;Nikitovic, D.;Tzanakakis, G. N.
通讯作者：
Tzanakakis, G. N.
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.