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

Alexander T.H. Wu, Prateeti Srivastava, Vijesh Kumar Yadav, David T.W. Tzeng, Sitthichai Iamsaard, Emily Chia Yu Su, Michael Hsiao, Ming Che Liu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number115109
Pages (from-to)115109
JournalToxicology and Applied Pharmacology
Volume401
DOIs
Publication statusPublished - Aug 15 2020

Keywords

  • Bladder Cancer
  • Extracellular Vesicle
  • M2 Tumor-Associated Macrophage
  • mTOR/CDK6/β-Catenin Signaling, Therapeutic Development
  • Ovatodiolide
  • Exosomes/drug effects
  • Coculture Techniques
  • Humans
  • Diterpenes/isolation & purification
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors
  • Mice, SCID
  • Urinary Bladder Neoplasms/drug therapy
  • Dose-Response Relationship, Drug
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • Macrophages/drug effects
  • Animals
  • Carcinogenesis/drug effects
  • Cell Line, Tumor
  • Female
  • Mice, Inbred NOD
  • beta Catenin/antagonists & inhibitors
  • Mice
  • MicroRNAs/antagonists & inhibitors
  • Plants, Medicinal

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this