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| 題名: | Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/β-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages |
| 作者: | 劉明哲
Alexander T.H. Wu, Prateeti Srivastava, Vijesh Kumar Yadav, David T.W. Tzeng, Sitthichai Iamsaard, Emily Chia-Yu Su, Michael Hsiao, Ming-Che Liu |
| 貢獻者: | 牙體技術學系 |
| 關鍵詞: | Keywords: Bladder Cancer;Ovatodiolide;M2 Tumor-Associated Macrophage;Extracellular Vesicle;mTOR/CDK6/β-Catenin Signaling, Therapeutic Development |
| 日期: | 2020-08 |
| 上傳時間: | 2025-04-01 21:30:57 (UTC+8) |
| 摘要: | Abstract:
Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and β-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and β-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV?+?CDDP combination both resulted in significant reductions in mTOR, β-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed β-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa. |
| 關聯: | Toxicology and Applied Pharmacology, Volume 401, 2020, 115109 |
| 描述: | 【109-2 升等】臺北醫學大學教師升等專門著作
職別：專任
送審等級：副教授
著作送審 |
| 資料類型: | article |
| 顯示於類別: | [教師升等送審著作] 109
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