School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, Jiangsu, China.
School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, Jiangsu, China.
Biochem Biophys Res Commun. 2019 May 14;512(4):819-824. doi: 10.1016/j.bbrc.2019.03.088. Epub 2019 Mar 28.
Emerging evidence has shown that metabolism, in particular the synthesis of fatty acids, has great significance for growth and metastasis of colorectal neoplasm. The previous results showed that RA-XII, a natural cyclopeptide isolated from Rubia yunnanensis, inhibits tumor growth and metastasis by AMPK/mTOR/P70S6K pathway and PI3K/AKT/NF-κB pathway. But if or not lipid metabolism involves the antitumor mechanism of RA-XII is not clear. Herein the results indicated that RA-XII reduced the cell motility by decreasing the expressions of β-catenin and β-catenin dependent proteins CD44 and MMP7 in HCT116 cells. Then RA-XII effectively reduced fatty acids levels by decreasing the expression of SREBP-1 and inhibiting the expressions of de novo fatty acid synthesis proteins FASN and SCD. Moreover the decreased cell motility caused by RA-XII was attenuated with the SREBP-1 knockdown. In addition, the in vivo experiments also demonstrated that RA-XII inhibited tumor growth and metastasis via restraining lipogenesis in colorectal neoplasm mouse models. Taken together, these results indicated that RA-XII suppressed the colorectal neoplasm growth and metastasis by inhibition of lipogenesis depended on SREBP-1 suppression.
新出现的证据表明，代谢，特别是脂肪酸的合成，对结直肠肿瘤的生长和转移具有重要意义。先前的结果表明，从云南茜草中分离得到的天然环肽 RA-XII 通过 AMPK/mTOR/P70S6K 通路和 PI3K/AKT/NF-κB 通路抑制肿瘤生长和转移。但是，脂质代谢是否涉及 RA-XII 的抗肿瘤机制尚不清楚。本研究结果表明，RA-XII 通过降低 HCT116 细胞中β-连环蛋白及其依赖的蛋白 CD44 和 MMP7 的表达来降低细胞迁移能力。然后，RA-XII 通过降低 SREBP-1 的表达并抑制从头合成脂肪酸的蛋白 FASN 和 SCD 的表达，有效地降低了脂肪酸水平。此外，通过 SREBP-1 敲低，可减弱 RA-XII 引起的细胞迁移能力降低。此外，体内实验还表明，RA-XII 通过抑制结直肠肿瘤小鼠模型中的脂生成来抑制肿瘤生长和转移。总之，这些结果表明，RA-XII 通过抑制 SREBP-1 抑制脂生成来抑制结直肠肿瘤的生长和转移。
