Wu Qi, Wang Shao-Ping, Sun Xiao-Xue, Tao Yu-Fan, Yuan Xiao-Qing, Chen Qi-Mei, Dai Long, Li Chun-Lei, Zhang Jia-Yu, Yang Ai-Lin
School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 510632, China.
Int J Biochem Cell Biol. 2022 Jan;142:106123. doi: 10.1016/j.biocel.2021.106123. Epub 2021 Nov 24.
Hepatocellular carcinoma (HCC) has become the sixth highly diagnosed cancer and the fourth main reason of cancer deaths worldwide. HuaChanSu, an extract from dried toad skin, exhibits good anticancer effects and has been widely used in the treatment of liver cancer. The reprogramming of glucose metabolism is one remarkable feature of hepatocellular carcinoma, and the effects of HuaChanSu on the abnormal glucose metabolism of cancer cells have not been elucidated. In our study, we investigate the effects of HuaChanSu on glucose metabolism of hepatocellular carcinoma cells and tumor growth in vivo. The results show that HuaChanSu inhibits the tumor growth of hepatoma H22-bearing mice and prolongs the survival time of tumor-bearing mice, additionally, HuaChanSu has no obvious adverse effects in these mice. In vitro, HuaChanSu restrains the proliferation, induces apoptosis and cell cycle arrest of human hepatoma cells. HuaChanSu also promotes ROS production and causes mitochondrial damage. Furthermore, HuaChanSu inhibits glucose uptake and lactate release in human hepatoma cells. Mechanistically, we find that HuaChanSu downregulates Hexokinase-2 (HK2) expression, and using RNA interference, we confirm that HuaChanSu suppresses the growth of HepG2 cells by interfering with glucose metabolism through downregulation of Hexokinase-2. However, knockdown of Hexokinase-2 has no obvious effect on the proliferation of SK-HEP-1 cells, although glucose uptake and lactate release are reduced in siHK2-transfected SK-HEP-1 cells, subsequently, we illustrate that two human hepatoma cell lines exhibit glucose metabolism heterogeneity, which causes the different cell proliferation responses to the inhibition of Hexokinase-2. Taken together, our study indicates that HuaChanSu could inhibit tumor growth and interfere with glucose metabolism via suppression of Hexokinase-2, and these findings provide a new insight into the anti-hepatoma mechanisms of HuaChanSu and lay a theoretical foundation for the further clinical application of HuaChanSu.
肝细胞癌（HCC）已成为全球第六大高诊断率癌症和第四大癌症死亡主要原因。华蟾素，一种从干蟾皮中提取的物质，具有良好的抗癌作用，已广泛用于肝癌治疗。葡萄糖代谢重编程是肝细胞癌的一个显著特征，而华蟾素对癌细胞异常葡萄糖代谢的影响尚未阐明。在我们的研究中，我们研究了华蟾素对肝癌细胞葡萄糖代谢和体内肿瘤生长的影响。结果表明，华蟾素可抑制荷肝癌H22小鼠的肿瘤生长并延长荷瘤小鼠的生存时间，此外，华蟾素对这些小鼠无明显不良反应。在体外，华蟾素抑制人肝癌细胞的增殖，诱导其凋亡并使细胞周期停滞。华蟾素还促进活性氧（ROS）生成并导致线粒体损伤。此外，华蟾素抑制人肝癌细胞的葡萄糖摄取和乳酸释放。机制上，我们发现华蟾素下调己糖激酶-2（HK2）表达，并且通过RNA干扰，我们证实华蟾素通过下调己糖激酶-2干扰葡萄糖代谢来抑制HepG2细胞的生长。然而，己糖激酶-2的敲低对SK-HEP-1细胞的增殖没有明显影响，尽管在转染siHK2的SK-HEP-1细胞中葡萄糖摄取和乳酸释放减少，随后，我们阐明两种人肝癌细胞系表现出葡萄糖代谢异质性，这导致对己糖激酶-2抑制的不同细胞增殖反应。综上所述，我们的研究表明华蟾素可通过抑制己糖激酶-2抑制肿瘤生长并干扰葡萄糖代谢，这些发现为华蟾素的抗肝癌机制提供了新的见解，并为华蟾素的进一步临床应用奠定了理论基础。
