State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 211198 Nanjing, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201 Kunming, China.
Molecules. 2019 May 12;24(9):1829. doi: 10.3390/molecules24091829.
Lipogenesis plays a critical role in the growth and metastasis of tumors, which is becoming an attractive target for anti-tumor drugs. RA-XII, one of the cyclopeptide glycosides isolated from , exerts anti-tumor effects on liver cancer. However, the underlying mechanisms are not clear. In the present study, the effects of RA-XII on lipogenesis were evaluated and the underlying mechanisms were investigated. The results indicated that RA-XII strongly inhibited tumor growth and lipogenesis (triglycerides and lipid droplets) in HepG2 cells, and the expression of key factors involved in lipogenesis (SREBP, SCD, FASN) was also obviously downregulated. Further investigation showed that the anti-tumor effects of RA-XII were attenuated by SREBP knockdown. Moreover, RA-XII downregulated the expression of SREBP cleavage-activating protein (SCAP), an upstream regulator of SREBP, and siRNA of SCAP prevented its restrained effects on tumor growth and lipogenesis. In addition, the in vivo experiment showed that RA-XII strongly restrained the lipogenesis and growth of liver tumor in nude mice xenograft model. Taken together, these results indicate that RA-XII suppresses the liver cancer growth by inhibition of lipogenesis via SCAP-dependent SREBP suppression. The findings reveal the potentials of RA-XII to be used in a novel therapeutic approach for treating liver cancer.
脂生成在肿瘤的生长和转移中起着关键作用，因此成为抗肿瘤药物的一个有吸引力的靶点。从 中分离得到的环肽糖苷之一 RA-XII 对肝癌具有抗肿瘤作用。然而，其潜在的机制尚不清楚。在本研究中，评估了 RA-XII 对脂生成的影响，并探讨了其潜在的机制。结果表明，RA-XII 强烈抑制 HepG2 细胞中的肿瘤生长和脂生成（甘油三酯和脂质滴），并且参与脂生成的关键因子（SREBP、SCD、FASN）的表达也明显下调。进一步的研究表明，SREBP 敲低减弱了 RA-XII 的抗肿瘤作用。此外，RA-XII 下调了 SREBP 的上游调节因子 SREBP 切割激活蛋白（SCAP）的表达，SCAP 的 siRNA 可阻止其对肿瘤生长和脂生成的抑制作用。此外，体内实验表明，RA-XII 可强烈抑制裸鼠异种移植模型中肝肿瘤的脂生成和生长。综上所述，这些结果表明，RA-XII 通过抑制 SCAP 依赖性 SREBP 抑制脂生成从而抑制肝癌的生长。这些发现揭示了 RA-XII 在治疗肝癌的新治疗方法中的应用潜力。
