College of Pharmacy, Sunchon National University, 255 Jungang-ro, Sunchon, Jeonnam, 57922, Republic of Korea.
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul, 03760, Republic of Korea.
Sci Rep. 2023 Feb 16;13(1):2811. doi: 10.1038/s41598-023-28773-z.
Endolichenic fungi are host organisms that live on lichens and produce a wide variety of secondary metabolites. Colorectal cancer stem cells are capable of self-renewal and differentiation into cancer cells, which makes cancers difficult to eradicate. New alternative therapeutics are needed to inhibit the growth of tumor stem cells. This study examined the ability of an extract of Jackrogersella sp. EL001672 (derived from the lichen Cetraria sp.) and the isolated compound 1'-O-methyl-averantin to inhibit development of cancer stemness. The endolichenic fungus Jackrogersella sp. EL001672 (KACC 83021BP), derived from Cetraria sp., was grown in culture medium. The culture broth was extracted with acetone to obtain a crude extract. Column chromatography and reverse-phase HPLC were used to isolate an active compound. The anticancer activity of the extract and the isolated compound was evaluated by qRT-PCR and western blotting, and in cell viability, spheroid formation, and reporter assays. The acetone extract of EL001672 did not affect cell viability. However, 1'-O-methyl-averantin showed cytotoxic effects against cancer cell lines at 50 μg/mL and 25 μg/mL. Both the crude extract and 1'-O-methyl-averantin suppressed spheroid formation in CRC cell lines, and downregulated expression of stemness markers ALDH1, CD44, CD133, Lgr-5, Msi-1, and EphB1. To further characterize the mechanism underlying anti-stemness activity, we examined sonic Hedgehog and Notch signaling. The results showed that the crude extract and the 1'-O-methyl-averantin inhibited Gli1, Gli2, SMO, Bmi-1, Notch-1, Hes-1, and the CSL complex. Consequently, an acetone extract and 1'-O-methyl-averantin isolated from EL001672 suppresses colorectal cancer stemness by regulating the sonic Hedgehog and Notch signaling pathways.
内生真菌是生活在地衣上并产生多种次生代谢物的宿主生物。结直肠癌细胞干细胞能够自我更新并分化为癌细胞，这使得癌症难以根除。需要新的替代疗法来抑制肿瘤干细胞的生长。本研究检查了 Jackrogersella sp. EL001672 提取物（源自地衣 Cetraria sp.）和分离得到的化合物 1'-O-甲基-averantin 抑制癌症干细胞特性发展的能力。内生真菌 Jackrogersella sp. EL001672（KACC 83021BP），源自 Cetraria sp.，在培养基中培养。用丙酮从培养液中提取得到粗提物。使用柱层析和反相高效液相色谱法分离活性化合物。通过 qRT-PCR 和 Western blot 以及细胞活力、球体形成和报告基因检测评估提取物和分离化合物的抗癌活性。EL001672 的丙酮提取物不影响细胞活力。然而，1'-O-甲基-averantin 在 50μg/mL 和 25μg/mL 时对癌细胞系表现出细胞毒性作用。粗提物和 1'-O-甲基-averantin 均抑制 CRC 细胞系球体形成，并下调干细胞标志物 ALDH1、CD44、CD133、Lgr-5、Msi-1 和 EphB1 的表达。为了进一步研究抗干细胞特性的作用机制，我们检查了 Sonic Hedgehog 和 Notch 信号通路。结果表明，粗提物和 1'-O-甲基-averantin 抑制 Gli1、Gli2、SMO、Bmi-1、Notch-1、Hes-1 和 CSL 复合物。因此，EL001672 中的丙酮提取物和 1'-O-甲基-averantin 通过调节 Sonic Hedgehog 和 Notch 信号通路抑制结直肠癌细胞的干细胞特性。
