Suppressive Effect of Delta-Tocotrienol on Hypoxia Adaptation of Prostate Cancer Stem-like Cells
Suppressive Effect of Delta-Tocotrienol on Hypoxia Adaptation of Prostate Cancer Stem-like Cells
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DOI：
10.21873/anticanres.12362
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发表时间：
2018-03-01
影响因子：
2
通讯作者：
Yano, Tomohiro
中科院分区：
文献类型：
--
作者：
Kaneko, Saki;Sato, Chiaki;Yano, Tomohiro
背景/目的：前列腺癌进展为晚期疾病的一个标志是获得雄激素非依赖性生长。这种恶性表型的特征在于对常规治疗的抗性，并且易于形成含有干细胞样癌细胞的缺氧区域。不幸的是，在缺氧条件下靶向前列腺癌干细胞的有效疗法尚未建立。在这份报告中，我们研究了δ-生育三烯酚（T3），一种表现出最有效抗癌活性的维生素E家族成员，是否可以抑制前列腺癌干细胞样细胞的存活。材料和方法：采用三维培养系统从PC 3亲本细胞中分离PC 3干细胞样细胞。通过在异种移植模型中评价对抗癌剂（多西他赛）的抗性和肿瘤形成能力，证实分离的PC 3干细胞样细胞的干细胞性。通过WST-8（细胞存活率）、实时逆转录聚合酶链反应（PCR）和蛋白质印迹法（western blotting）检测delta-T3对缺氧条件下PC 3干细胞样细胞的影响。结果如下：d-T3以剂量依赖性方式对前列腺癌干细胞样细胞表现出细胞毒性作用，并降低缺氧诱导因子（HIF）-1 α和HIF-2 α的蛋白水平。此外，针对HIF-1 α的特异性抑制剂诱导对PC 3细胞的细胞毒性，但选择性抑制HIF-2 α则没有效果。结论：总的来说，这些结果表明，delta-T3可以抑制前列腺癌干细胞样细胞在缺氧条件下的存活，主要是通过HIF-1 α信号转导的失活。
Background/Aim: A hallmark of the progression of prostate cancer to advanced disease is the acquisition of androgen-independent growth. This malignant phenotype is characterized by resistance to conventional treatments and predisposes to formation of hypoxic regions containing stem-like cancer cells. Unfortunately, an effective therapy to target prostate cancer stem cells under hypoxia has not yet been established. In this report, we studied whether delta-tocotrienol (T3), a vitamin E family member that has exhibited the most potent anti-cancer activity, could suppress the survival of prostate cancer stem-like cells. Materials and Methods: PC3 stem-like cells were isolated from PC3 parental cells using a three-dimensional culture system. The stemness of the isolated PC3 stem-like cells was confirmed by evaluation of resistance to an anticancer agent (docetaxel) and tumor formation capacity in a xenograft model. The effects of delta-T3 on PC3 stem-like cells under a hypoxia condition were examined by WST-8 (cell viability), real-time reverse transcription-polymerase chain reaction (PCR) and western blotting. Results: d-T3 demonstrated a cytotoxic effect on prostate cancer stem-like cells in a dose dependent manner and a reduction in the protein levels of hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha. Additionally, a specific inhibitor toward HIF-1 alpha induced cytotoxicity on PC3 cells, but selective inhibition of HIF-2 alpha had no effect. Conclusion: Overall, these results suggest that delta-T3 could inhibit the survival of prostate cancer stem-like cells under hypoxia, primarily through the inactivation of HIF-1 alpha signaling.