Linderapyrone analogue LPD-01 as a cancer treatment agent by targeting importin7

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Journal of Natural Medicines Pub Date : 2024-01-24 DOI:10.1007/s11418-023-01774-y

Takahiro Kitagawa, Takahiro Matsumoto, Tomoe Ohta, Tatsusada Yoshida, Youhei Saito, Yuji Nakayama, Yuki Hadate, Eishi Ashihara, Tetsushi Watanabe

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Abstract

The Wnt/β-catenin signaling pathway plays important roles in several cancer cells, including cell proliferation and development. We previously succeeded in synthesizing a small molecule compound inhibiting the Wnt/β-catenin signaling pathway, named LPD-01 (1), and 1 inhibited the growth of human colorectal cancer (HT-29) cells. In this study, we revealed that 1 inhibits the growth of HT-29 cells stronger than that of another human colorectal cancer (SW480) cells. Therefore, we have attempted to identify the target proteins of 1 in HT-29 cells. Firstly, we investigated the effect on the expression levels of the Wnt/β-catenin signaling pathway-related proteins. As a result, 1 inhibited the expression of target proteins of Wnt/β-catenin signaling pathway (c-Myc and Survivin) and their genes, whereas the amount of transcriptional co-activator (β-catenin) was not decreased, suggesting that 1 inhibited the Wnt/β-catenin signaling pathway without affecting β-catenin. Next, we investigated the target proteins of 1 using magnetic FG beads. Chemical pull-down assay combined with mass spectrometry suggested that 1 directly binds to importin7. As expected, 1 inhibited the nuclear translocation of importin7 cargoes such as Smad2 and Smad3 in TGF-β-stimulated HT-29 cells. In addition, the knockdown of importin7 by siRNA reduced the expression of target genes of Wnt/β-catenin signaling pathway. These results suggest that importin7 is one of the target proteins of 1 for inhibition of the Wnt/β-catenin signaling pathway.

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林达吡喃酮类似物 LPD-01 通过靶向导入素 7 作为癌症治疗药物。

Wnt/β-catenin 信号通路在多种癌细胞中发挥着重要作用，包括细胞增殖和发育。我们之前成功合成了一种抑制 Wnt/β-catenin 信号通路的小分子化合物，命名为 LPD-01（1），1 抑制了人类结直肠癌（HT-29）细胞的生长。在这项研究中，我们发现 1 对 HT-29 细胞生长的抑制作用比对另一种人类结直肠癌（SW480）细胞的抑制作用更强。因此，我们试图确定 1 在 HT-29 细胞中的靶蛋白。首先，我们研究了 1 对 Wnt/β-catenin 信号通路相关蛋白表达水平的影响。结果表明，1抑制了Wnt/β-catenin信号通路靶蛋白（c-Myc和Survivin）及其基因的表达，而转录共激活因子（β-catenin）的量并没有减少，这表明1抑制了Wnt/β-catenin信号通路，但没有影响β-catenin。接下来，我们利用磁性 FG 珠研究了 1 的靶蛋白。化学牵引试验结合质谱分析表明，1直接与importin7结合。不出所料，1抑制了TGF-β刺激的HT-29细胞中Smad2和Smad3等importin7载体的核转位。此外，通过 siRNA 敲除导入素 7 还能降低 Wnt/β-catenin 信号通路靶基因的表达。这些结果表明，导入素7是1抑制Wnt/β-catenin信号通路的靶蛋白之一。

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来源期刊

Journal of Natural Medicines 医学-药学

CiteScore

6.90

自引率

3.00%

发文量

审稿时长

1.7 months

期刊介绍： The Journal of Natural Medicines is an international journal publishing original research in naturally occurring medicines and their related foods and cosmetics. It covers: -chemistry of natural products -biochemistry of medicinal plants -pharmacology of natural products and herbs, including Kampo formulas and traditional herbs -botanical anatomy -cultivation of medicinal plants. The journal accepts Original Papers, Notes, Rapid Communications and Natural Resource Letters. Reviews and Mini-Reviews are generally invited.