iodoresiniferatoxin and Fibrosarcoma

Vanilloid receptor1 (VR1/TRPV1) is expressed on peripheral nerves and involved in sensing of temperature and pain. Recent reports have demonstrated that tumor cells express TRPV1 and that capsaicin (CP), a ligand for TRPV1, induces apoptosis in cancer cells. The mechanism underlying CP-induced tumor cell apoptosis remains unclear. Here, we investigated the role of TRPV1 in tumor apoptosis using TRPV1-expressing cancer cell lines. We demonstrate that iodo-resiniferatoxin (I-RTX), an antagonist of TRPV1 does not inhibit CP mediated apoptosis nor is it cytotoxic by itself, but acts as a partial agonist and shows synergistic effect with CP. We further demonstrate that CP treatment degrades Fas-associated factor1 (FAF1); a TRPV1 associated protein. Moreover, using RNA interference with small inhibitory RNAs (siRNA) for FAF1 we observed that down-regulation of FAF1 by siRNA makes the cell susceptible to enhanced apoptosis with CP. In summary, our data shows for the first time that the underlying mechanisms of CP-induced cancer cell apoptosis involves FAF1, a TRPV1 associated protein and serves as an important foundation for further understanding of anticancer activity of CP.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Capsaicin; Carrier Proteins; Caspase 3; Cell Line, Tumor; Diterpenes; Dose-Response Relationship, Drug; Drug Partial Agonism; Enzyme Activation; Fibrosarcoma; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred BALB C; Reactive Oxygen Species; RNA Interference; RNA, Messenger; Time Factors; Transfection; TRPV Cation Channels