2. Academic Validation
  3. CDK7 inhibition by THZ1 suppresses cancer stemness in both chemonaïve and chemoresistant urothelial carcinoma via the hedgehog signaling pathway

CDK7 inhibition by THZ1 suppresses cancer stemness in both chemonaïve and chemoresistant urothelial carcinoma via the hedgehog signaling pathway

  • Cancer Lett. 2021 Jun 1;507:70-79. doi: 10.1016/j.canlet.2021.03.012.
Po-Ming Chow 1,  Yu-Wei Chang 2,  Kuan-Lin Kuo 3,  Wei-Chou Lin 4,  Shing-Hwa Liu 5,  Kuo-How Huang 6
Affiliations

Affiliations

  • 1 Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address: [email protected].
  • 2 Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address: [email protected].
  • 3 Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan; Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address: [email protected].
  • 4 Department of Pathology, National Taiwan University Hospital, Taipei, 100, Taiwan. Electronic address: [email protected].
  • 5 Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan; Department of Pediatrics, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan. Electronic address: [email protected].
  • 6 Department of Urology, National Taiwan University Hospital, Taipei, 100, Taiwan; Department of Urology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan. Electronic address: [email protected].
PMID: 33741425 DOI: 10.1016/j.canlet.2021.03.012
Abstract

Urothelial carcinoma (UC) is the most common type of bladder Cancer, with a 5-year survival rate of only 4.6% in metastatic UC. Despite the advances related to immune-checkpoint inhibitor therapy, chemotherapy remains the standard of care for metastatic diseases, with a 50% response rate. The covalent cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 interferes with transcription machinery and is reported to be effective in cancers without targetable mutations. Therefore, we investigated the therapeutic effect of THZ1 on UC and examined possible mechanisms underlying its effects in both chemonaïve and chemosensitive cancers. CDK7 expression is increased in bladder Cancer tissues, especially in patients with chemoresistance. THZ1 induced Apoptosis and decreased viability in RT4, BFTC905, HT1376, T24, and T24/R UC cell lines. RNA-sequencing, immunoblotting, and sphere-formation assays confirmed that THZ1 suppressed Cancer stemness. In the mouse xenograft model, THZ1 suppressed both chemonaïve and chemoresistant tumors. These results indicate that CDK7 inhibition-related Cancer stemness suppression is a potential therapeutic strategy for both chemonaïve and chemoresistant UC.

Keywords

Apoptosis; Bladder cancer; Cancer stem cell; Cisplatin; Drug resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 Inhibitor
    CDK