title: Activation of endogenous TRPV1 fails to induce overstimulation-based cytotoxicity in breast and prostate cancer cells but not in pain-sensing neurons.
abstract: Vanilloids including capsaicin and resiniferatoxin are potent transient receptor potential vanilloid type 1 (TRPV1) agonists. TRPV1 overstimulation selectively ablates capsaicin-sensitive sensory neurons in animal models in vivo. The cytotoxic mechanisms are based on strong Na(+) and Ca(2+) influx via TRPV1 channels, which leads to mitochondrial Ca(2+) accumulation and necrotic cell swelling. Increased TRPV1 expression levels are also observed in breast and prostate cancer and derived cell lines. Here, we examined whether potent agonist-induced overstimulation mediated by TRPV1 might represent a means for the eradication of prostate carcinoma (PC-3, Du 145, LNCaP) and breast cancer (MCF7, MDA-MB-231, BT-474) cells in vitro. While rat sensory neurons were highly vanilloid-sensitive, normal rat prostate epithelial cells were resistant in vivo. We found TRPV1 to be expressed in all cancer cell lines at mRNA and protein levels, yet protein expression levels were significantly lower compared to sensory neurons. Treatment of all human carcinoma cell lines with capsaicin didn't lead to overstimulation cytotoxicity in vitro. We assume that the low vanilloid-sensitivity of prostate and breast cancer cells is associated with low expression levels of TRPV1, since ectopic TRPV1 expression rendered them susceptible to the cytotoxic effect of vanilloids evidenced by plateau-type Ca(2+) signals, mitochondrial Ca(2+) accumulation and Na(+)- and Ca(2+)-dependent membrane disorganization. Moreover, long-term monitoring revealed that merely the ectopic expression of TRPV1 stopped cell proliferation and often induced apoptotic processes via strong activation of caspase-3 activity. Our results indicate that specific targeting of TRPV1 function remains a putative strategy for cancer treatment.
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, Fribourg CH-1700, Switzerland. Electronic address: laszlo.pecze@unifr.ch.
authors.forename: László
authors.initials: L
authors.lastname: Pecze
authors.affiliation: Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6701, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Jósvay
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, Fribourg CH-1700, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Blum
authors.affiliation: Department of Surgery, Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: György
authors.initials: G
authors.lastname: Petrovics
authors.affiliation: Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged H-6701, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Vizler
authors.affiliation: Acheuron Hungary Ltd., Szeged H-6726, Hungary (e) Institute of Chemistry, Faculty of Material Science and Engineering, University of Miskolc, H-3515, Hungary; Institute of Chemistry, Faculty of Material Science and Engineering, University of Miskolc, H-3515, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Oláh
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, Fribourg CH-1700, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Schwaller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002211:Capsaicin / Q000494:pharmacology*; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012668:Trigeminal Ganglion / Q000378:metabolism
chemical_list: D004224:Diterpenes; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; C024353:resiniferatoxin; D002211:Capsaicin
keywords: Breast cancer; Ca(2+) signaling; Prostate cancer; TRPV1