Role of Cationic Channel TRPV2 in Promoting Prostate Cancer Migration and Progression to Androgen Resistance

Abstract

Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa. Cancer Res; 70(3); 1225-35. ©2010 AACR.

Blockade of TRPM8 activity reduces the invasion potential of oral squamous carcinoma cell lines

“…Invasive cells are reported to secrete proteolytic enzymes known as MMPs, such as MMP-2 and MMP-9, that degrade the basement membrane, which is mainly made up of type IV collagen (27,28). Elevated [Ca 2+ ] i is likely to be involved in the above mechanism since the constitutive activity of TRPV2, another TRP channel, reportedly increases the intracellular Ca 2+ level and promotes prostate cancer-cell invasion through MMP-9 activation (29). The present finding that menthol increases the gelatinase activity of MMP-9 while RQ suppresses it suggests that TRPM8-stimulation positively regulates MMP-9 activity, an inference in line with the TRPM8-induced increase in metastatic potential.…”

Involvement of TRPV2 Activation in Intestinal Movement through Nitric Oxide Production in Mice

“…However, TRPV2 mRNA or immunoreactivity has also been detected in the brain, autonomic ganglia, spinal cord, skeletal and vascular myocytes, visceral organs (including the intestine, pancreas, spleen, and bladder), and blood cells (Caterina et al, 1999;Ichikawa and Sugimoto, 2001;Muraki et al, 2003;Kashiba et al, 2004;Lewinter et al, 2004;Inada et al, 2006;Lewinter et al, 2008;Hisanaga et al, 2009;Zanou et al, 2009;Link et al, 2010). TRPV2 expression may also be involved in the migration and proliferation of cancer cells (Caprodossi et al, 2008;Monet et al, 2010), and TRPV2-positive neurons observed in the rat myenteric plexus may be IPANs (Kashiba et al, 2004). Mechanosensitivity of TRPV2 was first reported in cardiac myocytes (Muraki et al, 2003), and we have recently reported its expression and mechanosensitivity in developing sensory and motor neurons (Shibasaki et al, 2010).…”

TRPV2 (transient receptor potential cation channel, subfamily V, member 2)

“…The biotinylation studies as well as calcium imaging experiments in some works suggest its expression on the plasma membrane (Monet et al, 2009;Monet et al, 2010). It translocates from the cytoplasm to the plasma membrane upon ligand stimulation.…”

“…TRPV2 transcript levels are higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). TRPV2 channel is expressed in PC3 and DU-145 cell lines derived from bone and brain metastasis, respectively (Monet et al, 2009;Monet et al, 2010). TRPV2 protein is expressed in human hepatoblastoma (HepG2) cells (Vriens et al, 2004).…”

“…Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B (Monet et al, 2010).…”