Gaurav Kumar, PhD Dr. Abhijit De, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Sector-22, Kharghar, Navi Mumbai-410210, Maharashtra
Abstract: Keratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development.
Abstract: Polymeric black tea polyphenols (PBPs) have been shown to possess anti-tumor-promoting effects in two-stage skin carcinogenesis. However, their mechanisms of action are not fully elucidated. In this study, mechanisms of PBP-mediated antipromoting effects were investigated in a mouse model employing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Compared to controls, a single topical application of TPA to mouse skin increased the translocation of protein kinase C (PKC) from cytosol to membrane. Pretreatment with PBPs 1-3 decreased TPA-induced translocation of PKC isozymes (α, β, η, γ, ε) from cytosol to membrane, whereas PBPs 4 and 5 were less effective. The levels of PKCs δ and ζ in cytosol/membrane were similar in all the treatment groups. Complementary confocal microscopic evaluation showed a decrease in TPA-induced PKCα fluorescence in PBP-3-pretreated membranes, whereas pretreatment with PBP-5 did not show a similar decrease. Based on the experiments with specific enzyme inhibitors and phosphospecific antibodies, both PBP-3 and PBP-5 were observed to decrease TPA-induced level and/or activity of phosphatidylinositol 3-kinase (PI3K) and AKT1 (pS473). An additional ability of PBP-3 to inhibit site-specific phosphorylation of PKCα at all three positions responsible for its activation [PKCα (pT497), PKC PAN (βII pS660), PKCα/βII (pT638/641)] and AKT1 at the Thr308 position, along with a decrease in TPA-induced PDK1 protein level, correlated with the inhibition of translocation of PKC, which may impart relatively stronger chemoprotective activity to PBP-3 than to PBP-5. Altogether, PBP-mediated decrease in TPA-induced PKC phosphorylation correlated well with decreased TPA-induced NF-κB phosphorylation and downstream target proteins associated with proliferation, apoptosis, and inflammation in mouse skin. Results suggest that the antipromoting effects of PBPs are due to modulation of TPA-induced PI3K-mediated signal transduction.
Abstract: In the present study, post-treatment effects of dietary turmeric on markers related to apoptosis, cell proliferation, and inflammation in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch (HBP) tumors were investigated. Tumors were induced by applying 0.5% DMBA topically to the HBP three times per week for 12 weeks. After tumor development, half of the animals continued on the control diet and the other half were shifted to a 1% turmeric diet for 4 weeks. To rule out DMBA discontinuation as a cause of inhibition in tumor growth, DMBA treatment was continued during dietary exposure of turmeric in another set of animals until the end of the experiment. The turmeric diet inhibited tumor growth in animals with or without DMBA carcinogen treatment compared to the animals on the control diet. When compared to hamsters bearing tumors that remained on the control diet, the buccal pouches of hamsters bearing tumors receiving turmeric showed the following results: (1) decreased cell proliferation (diminished PCNA, cyclin D1, and Bcl-2) and PCNA labelling index, (2) enhanced apoptosis (increased Bax, caspase-3, caspase-9, and cytochrome c, and decreased survivin) and apoptotic index, (3) decreased inflammation (decreased Cox-2), and (4) decreased MAPK activation (p-ERK and p-p38). These data indicate that tumor growth decreased due to the modulation of cellular pathways associated with cell proliferation and apoptosis.
Abstract: Tea (Camellia sinensis), a popular beverage, is consumed worldwide. The biological activities and mechanism(s) of chemopreventive effects of green tea polyphenols (monomeric catechins) have been extensively studied, while similar information regarding newly formed major black tea polyphenols (BTPs-oligomeric, polymeric) is not available. Therefore, this review focuses mainly on compiling the evidence on chemopreventive efficacy of black tea extract (BTE) / BTPs and describing their mechanism(s) of anti-initiating, anti-promoting and anti-progressor action(s) in in vivo experimental systems. Overall, the mechanism(s) implicated in the BTPs-mediated inhibition are diverse and involve effects on multiple molecular pathways and genes.
