Tai Shun-Ban, Huang Chih-Yin, Chung Chih-Ling, Sung Ping-Jyun, Wen Zhi-Hong, Chen Chun-Lin
Departments of Marine Biotechnology and Resources (S.-B.T., Z.-H.W.) and Biological Sciences (C.-L.Chu., C.-L.Che.), National Sun Yat-Sen University, Kaohsiung, Taiwan; Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan (S.-B.T.); Department of Orthopaedics, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan (C.-y.H.); National Museum of Marine Biology and Aquarium, Pingtung, Taiwan (P.-J.S.); and Department of Biotechnology (C.-L.Che.) and Graduate Institute of Natural Products, College of Pharmacy (C.-L.Che.), Kaohsiung Medical University, Kaohsiung, Taiwan.
Departments of Marine Biotechnology and Resources (S.-B.T., Z.-H.W.) and Biological Sciences (C.-L.Chu., C.-L.Che.), National Sun Yat-Sen University, Kaohsiung, Taiwan; Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan (S.-B.T.); Department of Orthopaedics, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan (C.-y.H.); National Museum of Marine Biology and Aquarium, Pingtung, Taiwan (P.-J.S.); and Department of Biotechnology (C.-L.Che.) and Graduate Institute of Natural Products, College of Pharmacy (C.-L.Che.), Kaohsiung Medical University, Kaohsiung, Taiwan
Mol Pharmacol. 2024 Mar 14;105(4):286-300. doi: 10.1124/molpharm.123.000776.
Prodigiosin (PG) is a naturally occurring polypyrrole red pigment produced by numerous microorganisms including some and strains. PG has exhibited promising anticancer activity; however, the molecular mechanisms of action of PG on malignant cells remain ambiguous. Transforming growth factor- (TGF-) is a multifunctional cytokine that governs a wide array of cellular processes in development and tissue homeostasis. Malfunctions of TGF- signaling are associated with numerous human cancers. Emerging evidence underscores the significance of internalized TGF- receptors and their intracellular trafficking in initiating signaling cascades. In this study, we identified PG as a potent inhibitor of the TGF- pathway. PG blocked TGF- signaling by targeting multiple sites of this pathway, including facilitating the sequestering of TGF- receptors in the cytoplasm by impeding the recycling of type II TGF- receptors to the cell surface. Additionally, PG prompts a reduction in the abundance of receptors on the cell surface through the disruption of the receptor glycosylation. In human Caucasian lung carcinoma cells and human hepatocellular cancer cell line cells, nanomolar concentrations of PG substantially diminish TGF--triggered phosphorylation of Smad2 protein. This attenuation is further reflected in the suppression of downstream target gene expression, including those encoding fibronectin, plasminogen activator inhibitor-1, and N-cadherin. SIGNIFICANCE STATEMENT: Prodigiosin (PG) emerges from this study as a potent TGF-β pathway inhibitor, disrupting receptor trafficking and glycosylation and reducing TGF-β signaling and downstream gene expression. These findings not only shed light on PG's potential therapeutic role but also present a captivating avenue towards future anti-TGF-β strategies.
灵菌红素（PG）是一种天然存在的聚吡咯红色色素，由包括某些沙雷氏菌和链霉菌菌株在内的多种微生物产生。PG已表现出有前景的抗癌活性；然而，PG对恶性细胞的分子作用机制仍不明确。转化生长因子-β（TGF-β）是一种多功能细胞因子，在发育和组织稳态中调控广泛的细胞过程。TGF-β信号传导功能异常与多种人类癌症相关。新出现的证据强调了内化的TGF-β受体及其细胞内运输在启动信号级联反应中的重要性。在本研究中，我们确定PG是TGF-β通路的有效抑制剂。PG通过靶向该通路的多个位点来阻断TGF-β信号传导，包括通过阻止II型TGF-β受体循环至细胞表面来促进其在细胞质中的隔离。此外，PG通过破坏受体糖基化促使细胞表面受体丰度降低。在人高加索肺癌细胞和人肝癌细胞系细胞中，纳摩尔浓度的PG可显著降低TGF-β触发的Smad2蛋白磷酸化。这种减弱进一步反映在下游靶基因表达的抑制上，包括那些编码纤连蛋白、纤溶酶原激活物抑制剂-1和N-钙黏蛋白的基因。意义声明：本研究表明灵菌红素（PG）是一种有效的TGF-β通路抑制剂，可破坏受体运输和糖基化，降低TGF-β信号传导和下游基因表达。这些发现不仅揭示了PG的潜在治疗作用，也为未来抗TGF-β策略提供了一条引人入胜的途径。
