1. Triggering of transient receptor potential vanilloid type 1 (TRPV1) by capsaicin induces Fas/CD95-mediated apoptosis of urothelial cancer cells in an ATM-dependent manner
- Author
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Sara Caprodossi, Roberta Lucciarini, Patrizia Ballarini, Massimo Nabissi, Giorgio Santoni, Marco Andrea Cardarelli, Maria Beatrice Morelli, Gabriele Mammana, and Consuelo Amantini
- Subjects
Cancer Research ,Programmed cell death ,Blotting, Western ,TRPV1 ,Fluorescent Antibody Technique ,TRPV Cation Channels ,Apoptosis ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Protein Serine-Threonine Kinases ,Fas ligand ,Downregulation and upregulation ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,fas Receptor ,Cells, Cultured ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Suppressor Proteins ,Cell Cycle ,General Medicine ,Fas receptor ,Flow Cytometry ,DNA-Binding Proteins ,Antigens, CD95 ,Capsaicin ,Protein-Serine-Threonine Kinases ,Sensory System Agents ,Urinary Bladder Neoplasms ,Urothelium ,Cancer research ,Receptor clustering - Abstract
Herein, we provide evidence on the expression of transient receptor potential vanilloid type 1 (TRPV1) on human urothelial cancer (UC) cells and its involvement in the apoptosis induced by the selective agonist capsaicin (CPS). We analyzed TRPV1 messenger RNA and protein expression on human UC cell lines demonstrating its progressive decrease in high-grade UC cells. Treatment of RT4 cells with CPS induced cell cycle arrest in G(0)/G(1) phase and apoptosis. These events were associated with rapid co-ordinated transcription of pro-apoptotic genes including Fas/CD95, Bcl-2 and caspase families and ataxia telangiectasia mutated (ATM)/CHK2/p53 DNA damage response pathway. CPS induced Fas/CD95 upregulation, but more importantly Fas/CD95 ligand independent, TRPV1-dependent death receptor clustering and triggering of both extrinsic and intrinsic mitochondrial-dependent pathways. Moreover, we observed that CPS activates ATM kinase that is involved in Ser15, Ser20 and Ser392 p53 phosphorylation as shown by the use of the specific inhibitor KU55933. Notably, ATM activation was also found to control upregulation of Fas/CD95 expression and its co-clustering with TRPV1 as well as RT4 cell growth and apoptosis. Altogether, we describe a novel connection between ATM DNA damage response pathway and Fas/CD95-mediated intrinsic and extrinsic apoptotic pathways triggered by TRPV1 stimulation on UC cells.
- Published
- 2009