Abstract 3683: Bioactive phytochemical proanthocyanidins target β-catenin signaling in preventing invasive potential of human melanoma cells.
Authors: Katiyar Santosh K. , Vaid Mudit 
Published: August 2014

Melanoma is the leading cause of death from skin diseases due to its propensity to metastasize. The overall incidence of melanoma is increasing in US, and is increasing rapidly in children. Since, melanoma is a highly malignant cancer with a potent capacity to metastasize distantly, an approach that decreases its metastatic potential may facilitate the development of an effective strategy for its prevention or treatment. Metastatic melanoma is often associated with activation of Wnt/β-catenin signaling pathway. To develop newer and more effective strategies for the prevention of melanoma metastasis, we have examined the inhibitory effect of proanthocyanidins, bioactive components of grape seeds, on cell migration of metastasis-specific human melanoma cell lines (A375 and Hs294t) and assessed whether Wnt/β-catenin signaling is the target of grape seed proanthocyanidins (GSPs). Using an in vitro invasion assay, we found that treatment of human melanoma cell lines with GSPs resulted in a dose-dependent inhibition of cell migration, which was associated with the degradation of cytosolic β-catenin, and subsequently reducing the nuclear accumulation of β-catenin (i.e., inactivation of β-catenin) and reducing the levels of matrix metalloproteinase (MMP) -2 and MMP-9 which are the down-stream targets of β-catenin and play a crucial role in cancer cell metastasis. GSPs increased the: (i) levels of casein kinase 1α, glycogen synthase kinase-3β and phosphorylated-β-catenin on critical serine residues (Ser45, Ser33/37 and Thr41), and (ii) binding of β-transducin repeat-containing proteins (β-TrCP) with phospho forms of β-catenin in melanoma cells. These molecular events lead to degradation and/or inactivation of β-catenin. To verify whether β-catenin is a potent molecular target of GSPs, the effect of GSPs was determined on β-catenin-activated (Mel1241) and β-catenin-inactivated (Mel1011) melanoma cells. Treatment of Mel1241 cells with GSPs or FH535, an inhibitor of Wnt/β-catenin pathway, significantly inhibited cell migration of Mel1241 cells, which was associated with the elevated levels of casein kinase 1α and glycogen synthase kinase-3β, and decreased accumulation of nuclear β-catenin and inhibition of MMP-2 and MMP-9 levels. However, this effect of GSPs and FH535 was not found in Mel1011 melanoma cells. These results indicate for the first time that grape seed proanthocyanidins inhibit the invasive potential of melanoma cells by targeting β-catenin signaling. This new insight into the anti-melanoma cell migration activity of GSPs could serve as the basis for chemoprevention or therapy of malignant melanoma in high risk human population.

Citation Format: Santosh K. Katiyar, Mudit Vaid. Bioactive phytochemical proanthocyanidins target β-catenin signaling in preventing invasive potential of human melanoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3683. doi:10.1158/1538-7445.AM2013-3683