HIF1α Regulates mTOR Signaling and Viability of Prostate Cancer Stem Cells
HIF1α Regulates mTOR Signaling and Viability of Prostate Cancer Stem Cells
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DOI：
10.1158/1541-7786.mcr-14-0153-t
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发表时间：
2015-03-01
影响因子：
5.2
通讯作者：
Horak, Peter
中科院分区：
文献类型：
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作者：
Marhold, Maximilian;Tomasich, Erwin;Horak, Peter
启动肿瘤的癌细胞亚群，也被称为癌症干细胞(CSC)，最近在前列腺癌中被发现和表征。采用一种典型的小鼠前列腺癌模型，研究了低氧诱导因子1a(HIF1a/HIF1α)在CSCs中的调节作用，并在HIF1a高表达的小鼠前列腺癌中鉴定出一个基本干细胞亚群(LIN(-)/SCA-1(+)/CD49f(+))。为了进一步分析低氧上调对干细胞增殖和HIF1α信号转导的影响，分离和鉴定了小鼠TRAMP-C1细胞(SCA-1(+)/CD49f(+))和人前列腺癌细胞系(CD44(+)/CD49f(+))的CSC亚群。缺氧CSC样细胞HIF1α水平和HIF靶基因表达增加，AKT表达上调是通过mTOR/S6K/IRS-1反馈环机制实现的。有趣的是，前列腺CSCs对选择性mTOR抑制剂的耐药性是由于HIF1α上调所致。因此，前列腺癌干细胞表现出一种通过IRS-1反馈抑制AKT信号的缺氧性失活。根据这些结果，我们认为，通过HIF1α解除PI3K/AKT/mTOR通路的调控对于CSC的静止和维持至关重要，它通过mTOR抑制CSC的代谢和生长，并通过AKT信号促进存活。我们还提出，前列腺CSCs可以对选择性mTOR抑制剂表现出原发耐药性。
Tumor-initiating subpopulations of cancer cells, also known as cancer stem cells (CSC), were recently identified and characterized in prostate cancer. A well-characterized murine model of prostate cancer was used to investigate the regulation of hypoxia-inducible factor 1a (HIF1A/HIF1 alpha) in CSCs and a basal stem cell subpopulation (Lin(-)/Sca-1(+)/CD49f(+)) was identified, in primary prostate tumors of mice, with elevated HIF1a expression. To further analyze the consequences of hypoxic upregulation on stem cell proliferation and HIF1 alpha signaling, CSC subpopulations from murine TRAMP-C1 cells (Sca-1(+)/CD49f(+)) as well as from a human prostate cancer cell line (CD44(+)/CD49f(+)) were isolated and characterized. HIF1 alpha levels and HIF target gene expression were elevated in hypoxic CSC-like cells, and upregulation of AKT occurred through a mechanism involving an mTOR/S6K/IRS-1 feedback loop. Interestingly, resistance of prostate CSCs to selective mTOR inhibitors was observed because of HIF1 alpha upregulation. Thus, prostate CSCs show a hypoxic deactivation of a feedback inhibition of AKT signaling through IRS-1. In light of these results, we propose that deregulation of the PI3K/AKT/mTOR pathway through HIF1 alpha is critical for CSC quiescence and maintenance by attenuating CSC metabolism and growth via mTOR and promoting survival by AKT signaling. We also propose that prostate CSCs can exhibit primary drug resistance to selective mTOR inhibitors.