Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation.
Dual-Blocking of PI3K and mTOR Improves Chemotherapeutic Effects on SW620 Human Colorectal Cancer Stem Cells by Inducing Differentiation.
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DOI：
10.3346/jkms.2016.31.3.360
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发表时间：
2016-03
影响因子：
4.5
通讯作者：
Kim CW
中科院分区：
文献类型：
--
作者：
Kim MJ;Koo JE;Han GY;Kim B;Lee YS;Ahn C;Kim CW
肿瘤干细胞(CSCs)在包括结直肠癌在内的多种肿瘤中具有肿瘤起始、自我更新、转移和化疗耐药等特性。靶向CSCs可能是防止化疗后肿瘤复发的关键。磷脂酰肌醇-3-激酶(PI3K)和哺乳动物雷帕霉素靶标(MTOR)信号是细胞生长、增殖、分化和凋亡的中枢调节因子。这些通路与结直肠肿瘤的发生有关。本研究通过抑制PI3K和mTOR通路启动SW620来源的CSCs的分化，并探讨其在肿瘤进展中的作用。分别用雷帕霉素、LY294002和NVP-BEZ235阻断结直肠癌细胞的PI3K和mTOR信号。结直肠癌干细胞获得了分化特性，但在双重阻断的CSCs中失去了茎的特性。用抗癌药物紫杉醇处理后，对分化后的CSCs细胞活力、自我更新能力和分化状态进行分析。因此，双封闭组对抗癌药物的敏感性最高。用免疫缺陷小鼠进行的移植瘤成瘤实验也表明，与单一抑制组相比，双重抑制组更有效地提高了药物敏感性，抑制了肿瘤生长。因此，PI3K和mTOR双阻断可诱导SW620人结直肠癌细胞分化，提高化疗效果，可能具有较强的抗癌作用。
Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs.