期刊
BRITISH JOURNAL OF CANCER
卷 111, 期 2, 页码 375-385出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2014.281
关键词
dichloroacetate; hyperpolarised C-13-MRS; H-1-MRS; autophagy; monocarboxylate transporter-1 inhibitor; [1-C-13]pyruvate; pyruvate to lactate exchange rate
类别
资金
- CRUK
- EPSRC Cancer Imaging Centre [C1060/A10334]
- CRUK [C1060/A16464]
- NHS
- Chang Gung Medical Foundation (Taiwan) [CMRPG370441]
- MRC [MRC119X]
- EPSRC [EP/H046526/1] Funding Source: UKRI
- MRC [G0701533] Funding Source: UKRI
- Cancer Research UK [16464, 11562] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [GR/S23612/01, EP/H046526/1] Funding Source: researchfish
- Medical Research Council [1100738, G0701533] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10162] Funding Source: researchfish
Background: Dichloroacetate (DCA) has been found to have antitumour properties. Methods: We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, H-1 and hyperpolarised C-13-magnetic resonance spectroscopy. Results: Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-C-13] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo. Conclusions: DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据