Department of Pharmacology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, PR China.
Biochem Biophys Res Commun. 2012 Jun 22;423(1):26-31. doi: 10.1016/j.bbrc.2012.05.053. Epub 2012 May 17.
Sirt3 is a member of the mammalian sirtuin family that is localized to mitochondria and plays a role in the control of the metabolic activity. Recently, Sirt3 has been reported to be associated with the deregulating metabolism of cancer cells. However, the role of Sirt3 in hepatocellular carcinoma (HCC) has never been studied. In this study, we found that Sirt3 protein expression was downregulated in human HCC tissue. We also showed that overexpression of Sirt3 using adenovirus inhibited HCC cell growth (two cell lines: HepG2 and HuH-7 cells) and induced apoptosis, which was evidenced by the increase of LDH leakage, enhancement of TUNEL-positive cells number and promotion of AIF translocation to nuclei. Sirt3 overexpression reduced the intracellular NAD(+) level, repressed the ERK1/2 signaling pathway, and activated the Akt and JNK signaling pathways. Furthermore, Sirt3 overexpression upregulated p53 protein level through downregulating Mdm2 and thereby slowing p53 degradation. Collectively, our data suggests that Sirt3 may play an important role in HCC development and progression and may be a promising therapeutic target for HCC.
Sirt3 是哺乳动物沉默调节蛋白家族的一员，定位于线粒体，在代谢活性的控制中发挥作用。最近，Sirt3 被报道与癌细胞代谢的失调有关。然而，Sirt3 在肝细胞癌 (HCC) 中的作用从未被研究过。在这项研究中，我们发现 Sirt3 蛋白表达在人 HCC 组织中下调。我们还表明，使用腺病毒过表达 Sirt3 抑制 HCC 细胞生长（两种细胞系：HepG2 和 HuH-7 细胞）并诱导细胞凋亡，这表现在 LDH 漏出增加、TUNEL 阳性细胞数量增加以及 AIF 向细胞核易位增加。Sirt3 过表达降低细胞内 NAD+水平，抑制 ERK1/2 信号通路，激活 Akt 和 JNK 信号通路。此外，Sirt3 过表达通过下调 Mdm2 而上调 p53 蛋白水平，从而减缓 p53 的降解。总之，我们的数据表明，Sirt3 可能在 HCC 的发展和进展中发挥重要作用，可能是 HCC 的一个有前途的治疗靶点。
