Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes ...associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33-34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase-scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca.sup.2+ signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Introduction and Hypothesis: Prostate cancer (PCa) is the most common internal malignancy and the second most frequent cause of cancer death in Canadian men. Capsaicin recently investigated ...for its anti-cancer properties, is the active compound found in chilli peppers. Well-established as a pain reliever, capsaicin acts mainly on the transient receptor potential vanilloid (TRPV)-1 and TRPV6 receptor. The TRPV1 receptor is a non-selective cation channel that induces an inflow of cations Ca2+ and Na+ when activated. Similarly, activation of the TRPV6 receptor facilitates Ca2+ entry across the plasma membrane. Both TRPV1 and TRPV6 receptors are expressed in PCa tissue. Our present study aims to investigate the chemopreventive effect of capsaicin in combination with lycopene, an antioxidant found in tomatoes. We have found that PCa cells treated with capsaicin and lycopene alone and combined, cause a significant reduction in proliferation and an induction of apoptosis. Mechanistic studies examining this relationship have not been well defined. We hypothesize that capsaicin and lycopene in combination reduce proliferation and induce apoptosis via the TRPV6 and TRPV1 receptor in PCa cells in vitro.
Materials and Methods: Two human PCa cell lines (LNCaP (AR+) and PC3 (AR-)) were analyzed. Cells were treated with capsaicin alone, or in combination with lycopene. Cells were incubated for up to 24 hours and proliferation assessed using MTS assay. Alterations in TRPV6, TRPV1, PSA, cell-regulatory molecules, and apoptotic markers were assessed by Western blot analysis.
Results: There was a significant (P< 0.05) decrease in the proliferation of LNCaP and PC3 cells treated with capsaicin alone and in combination with lycopene (p< 0.001). Western blot analysis revealed a reduction (2-fold change) in PSA expression in LNCaP cells when treated with capsaicin alone. Interestingly this treatment resulted in the up-regulation in cell cycle marker p27 as well as cleaved PARP, in a time-dependent manner, demonstrating that the cells are undergoing cell cycle arrest and apoptosis. Further, we established that there is an up-regulation (3-fold change) of TRPV6 expression and an increase in TRPV1 expression with the treatment of capsaicin and lycopene alone and in combination. A plausible mechanism of action for this combination of capsaicin and lycopene is currently being investigated.
Conclusions: We have shown for the first time that the TRPV6 receptor may play an important role in capsaicin and lycopene mediated cell-cycle arrest and apoptosis in human PCa cells. These studies may eventually help identify patients likely to benefit from the use of capsaicin in combination with lycopene. Ultimately these strategies may have a more meaningful impact on PCa morbidity and mortality than other therapeutic strategies currently in use.
Funding: CIHR grant to VV.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5724.
PDF
