Berberine inhibits colorectal tumor growth by suppressing SHH secretion

• Published in: Acta pharmacologica Sinica Vol. 42; no. 7; pp. 1190 - 1194
• Main Authors: Shen, Zhu-qing, Wang, Juan, Tan, Wen-fu, Huang, Tao-min
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.07.2021; Nature Publishing Group
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Antitumor activity; Berberine; Berberine - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Gene expression; Hedgehog protein; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Immunology; Internal Medicine; Kinases; Medical Microbiology; Mice; Mice, Inbred BALB C; Mice, Nude; Oral administration; Paracrine signalling; Pharmacology/Toxicology; RNA - metabolism; RNA Stability - drug effects; Secretion; Signal transduction; Signal Transduction - drug effects; Stromal cells; Vaccine; Vascular endothelial growth factor; Vascularization; Xenograft Model Antitumor Assays; Xenografts; GDC-0449; Robotnikinin; actinomycin D; Hedgehog; colorectal cancer; sonic hedgehog (SHH); tumor; BAY11-7082; berberine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-020-00514-2

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 − 1  · d −1 ) or a positive control drug GDC-0449 (100 mg · kg −1  · d −1 ) 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.