Department of Pharmacy, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Acta Pharmacol Sin. 2021 Jul;42(7):1190-1194. doi: 10.1038/s41401-020-00514-2. Epub 2020 Sep 21.
Hedgehog plays an important role in a wide range of physiological and pathological conditions. Paracrine activation of Hedgehog pathway in stromal cells increases the expression of VEGF, which promotes neovascularization in colorectal cancer and ultimately the growth of colorectal cancer. Berberine (BBR) has anticancer activity. In this study we investigated whether BBR inhibited the growth of colon cancer through suppressing the paracrine sonic hedgehog (SHH) signaling in vitro and in vivo. We showed that BBR (1-10 μM) dose-dependently inhibited the secretion and expression of SHH protein in HT-29 and SW480 cells. BBR did not influence the transcription of SHH, but promoted the degradation of SHH mRNA, thus decreased the SHH mRNA expression in the colorectal cancer cells. In nude mice bearing HT-29 xenograft, oral administration of BBR (100 mg · kg · d) or a positive control drug GDC-0449 (100 mg · kg · d) for 4 weeks markedly suppressed the growth of HT-29 tumor with BBR exhibiting a better antitumor efficacy. The tumor growth inhibition caused by BBR or GDC-0449 was comparable to their respective inhibitory effect on the mouse-specific Gli mRNA expression in the tumor. However, BBR (20 μM) did not affect the expression of human transcription factor Gli1 mRNA in HT-29 and SW480 cells. In conclusion, BBR promotes the degradation of SHH mRNA in colorectal cancer cells, interrupting the paracrine Hedgehog signaling pathway activity thus suppresses the colorectal cancer growth. This study reveals a novel molecular mechanism underlying the anticancer action of BBR.
Hedgehog 在广泛的生理和病理条件下发挥着重要作用。基质细胞中 Hedgehog 途径的旁分泌激活增加了 VEGF 的表达，促进了结直肠癌的新生血管形成，最终促进了结直肠癌的生长。小檗碱（BBR）具有抗癌活性。本研究旨在探讨 BBR 是否通过抑制体外和体内旁分泌 sonic hedgehog（SHH）信号来抑制结肠癌的生长。结果表明，BBR（1-10 μM）剂量依赖性地抑制 HT-29 和 SW480 细胞中 SHH 蛋白的分泌和表达。BBR 不影响 SHH 的转录，但促进 SHH mRNA 的降解，从而降低结直肠癌细胞中 SHH mRNA 的表达。在携带 HT-29 异种移植物的裸鼠中，口服 BBR（100 mg·kg·d）或阳性对照药物 GDC-0449（100 mg·kg·d）4 周可显著抑制 HT-29 肿瘤的生长，BBR 表现出更好的抗肿瘤疗效。BBR 或 GDC-0449 引起的肿瘤生长抑制与它们各自对肿瘤中鼠特异性 Gli mRNA 表达的抑制作用相当。然而，BBR（20 μM）并不影响 HT-29 和 SW480 细胞中人类转录因子 Gli1 mRNA 的表达。总之，BBR 促进结直肠癌细胞中 SHH mRNA 的降解，阻断旁分泌 Hedgehog 信号通路活性，从而抑制结直肠癌的生长。该研究揭示了 BBR 抗癌作用的新分子机制。
