Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan.
Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
J Nat Med. 2022 Jan;76(1):110-118. doi: 10.1007/s11418-021-01560-8. Epub 2021 Aug 31.
Breast cancer is the most commonly diagnosed cancer among women worldwide. Despite a variety of drugs available for the treatment of patients with breast cancer, drug resistance remains a significant clinical problem. Therefore, there is an urgent need to develop drugs with new mechanisms of action. Camalexin is the main indole phytoalexin in Arabidopsis thaliana and other crucifers. Camalexin inhibits the proliferation of various cancer cells. However, the mechanism by which camalexin inhibits cell proliferation remains unclear. In this study, we found that camalexin inhibited cell proliferation and migration of breast cancer cell lines. Furthermore, camalexin also suppressed breast cancer stem cell-derived mammosphere formation. We previously reported that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) agonist suppresses mammosphere formation. Several compounds with indole structures are known to act as AhR agonists. Therefore, we hypothesized that the inhibition of mammosphere formation by camalexin may involve AhR activation. We found that camalexin increased the nuclear translocation of AhR, AhR-mediated transcriptional activation, and expression of AhR target genes. In addition, camalexin suppressed mammosphere formation in AhR-expressing breast cancer cells more than in the breast cancer cells that lacked AhR expression. Taken together, the data demonstrate that camalexin is a novel AhR agonist and that the inhibition of cell proliferation, migration, and mammosphere formation by camalexin involves the activation of AhR. Our findings suggest that camalexin, an AhR agonist, may be a novel therapeutic agent for breast cancer.
乳腺癌是全球女性中最常见的癌症。尽管有多种药物可用于治疗乳腺癌患者，但耐药性仍然是一个重大的临床问题。因此，迫切需要开发具有新作用机制的药物。卡马莱辛是拟南芥和其他十字花科植物中的主要吲哚植物抗毒素。卡马莱辛抑制各种癌细胞的增殖。然而，卡马莱辛抑制细胞增殖的机制尚不清楚。在这项研究中，我们发现卡马莱辛抑制乳腺癌细胞系的增殖和迁移。此外，卡马莱辛还抑制乳腺癌干细胞来源的乳腺球体形成。我们之前报道过，配体激活的转录因子芳香烃受体（AhR）激动剂抑制乳腺球体形成。几种具有吲哚结构的化合物已知具有 AhR 激动剂的作用。因此，我们假设卡马莱辛抑制乳腺球体形成可能涉及 AhR 激活。我们发现卡马莱辛增加了 AhR 的核转位、AhR 介导的转录激活和 AhR 靶基因的表达。此外，卡马莱辛在表达 AhR 的乳腺癌细胞中比在缺乏 AhR 表达的乳腺癌细胞中更能抑制乳腺球体形成。综上所述，数据表明卡马莱辛是一种新型的 AhR 激动剂，卡马莱辛通过激活 AhR 抑制细胞增殖、迁移和乳腺球体形成。我们的研究结果表明，AhR 激动剂卡马莱辛可能是一种治疗乳腺癌的新型治疗剂。
