3-溴丙酮酸诱导内质网应激，克服自噬并导致人肝癌细胞系凋亡。
3-Bromopyruvate induces endoplasmic reticulum stress, overcomes autophagy and causes apoptosis in human HCC cell lines.
机构信息
Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock Building, Room 545, Baltimore, MD 21287, USA.
出版信息
Anticancer Res. 2010 Mar;30(3):923-35.
BACKGROUND
Autophagy, a cellular response to stress, plays a role in resistance to chemotherapy in cancer cells. Resistance renders systemic chemotherapy generally ineffective against human hepatocellular carcinoma (HCC). Recently, we reported that the pyruvate analog 3-bromopyruvate (3-BrPA) promoted tumor cell death by targeting GAPDH. In continuance, we investigated the intracellular response of two human HCC cell lines (Hep3B and SK-Hep1) that differ in their status of key apoptotic regulators, p53 and Fas.
METHODS AND RESULTS
3-BrPA treatment induced endoplasmic reticulum (ER) stress, translation inhibition and apoptosis based on Western blot and qPCR, pulse labeling, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and active caspase-3 in both the cell lines. However, electron microscopy revealed that 3-BrPA treated SK-Hep1 cells underwent classical apoptotic cell death while Hep3B cells initially responded with the protective autophagy that failed to prevent eventual apoptosis.
CONCLUSION
3-BrPA treatment promotes apoptosis in human HCC cell lines, irrespective of the intracellular response.
背景
自噬是细胞对压力的一种反应，在癌细胞对化疗的耐药性中起作用。耐药性使全身性化疗对人肝癌（HCC）通常无效。最近，我们报道了丙酮酸类似物 3-溴丙酮酸（3-BrPA）通过靶向 GAPDH 促进肿瘤细胞死亡。在此基础上，我们研究了两种人 HCC 细胞系（Hep3B 和 SK-Hep1）的细胞内反应，这两种细胞系在关键凋亡调节剂 p53 和 Fas 的状态上存在差异。
方法和结果
3-BrPA 处理诱导内质网（ER）应激、翻译抑制和凋亡，Western blot 和 qPCR、脉冲标记、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测和活性 caspase-3 在两种细胞系中均有体现。然而，电子显微镜显示，3-BrPA 处理的 SK-Hep1 细胞经历了经典的凋亡细胞死亡，而 Hep3B 细胞最初则表现出保护性自噬，但未能阻止最终的凋亡。
结论
3-BrPA 处理促进了人肝癌细胞系的凋亡，而与细胞内反应无关。
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