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Carcinogenesis Advance Access published online on June 5, 2009
Carcinogenesis, doi:10.1093/carcin/bgp138
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Consuelo Amantini1, Patrizia Ballarini2, Sara Caprodossi1, Massimo Nabissi1, Maria Beatrice Morelli1,5, Roberta Lucciarini1, Marco Andrea Cardarelli3, Gabriele Mammana4 and Giorgio Santoni1

1 Department of Experimental Medicine and Public Health, University of Camerino
2 Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino (MC), Italy
3 Pathology and Cytodiagnostic Unit, ASUR 9
4 Urology Operative Unit, ASUR 9, Macerata, Italy
5 Department of Experimental Medicine, University "La Sapienza", Rome, Italy

Author correspondence: Prof. Giorgio Santoni, Dept. Experimental Medicine and Public Health, University of Camerino, Via Madonna delle carceri 9, 62032 Camerino, Italy, Phone: 39 0737 403312/403319, Fax: 39 0737 403325, E-mail: giorgio.santoni{at}unicam.it

Herein, we provide evidence on the expression of TRPV1 on human urothelial cancer cells (UC), and its involvement in the apoptosis induced by the selective agonist capsaicin (CPS).

We analyzed TRPV1 mRNA 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 G0/G1 phase and apoptosis. These events were associated with rapid coordinated transcription of pro-apoptotic genes including Fas/CD95, Bcl-2 and caspase families and ATM/CHK2/p53 DNA damage response pathway. CPS induced Fas/CD95 up-regulation, 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 up-regulation 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.

Key Words: Urothelial cancer • Transient Receptor Potential Vanilloid Type-1 • Apoptosis • Fas/CD95 • ATM

Received February 2, 2009; revised May 26, 2009; accepted May 28, 2009.


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