cyclin-d1 and kaempferol

Kaempferol has been reported to play an anti-tumor role in various human cancers, while its role in gallbladder cancer (GBC) is unclear.. We found that kaempferol significantly inhibited the growth, invasion and migration, meanwhile induced apoptosis through cells arrested at G0/G1 phase of GBC cell lines, including GBC-SD and SGC996 cells in vitro.. Kaempferol promoted the release of cytochrome C from the mitochondria to cytoplasm, the activation of c-caspase-3 and c-caspase-9 and increased the expression levels of pro-apoptotic factor Bax, meanwhile decreased the expression levels of anti-apoptotic factor Bcl-2. In addition, the expression levels of CDK4, CDK6 and cyclin D1, which are members of the CDK4/CDK6/cyclin D1 signaling pathway, were also decreased by kaempferol. Moreover, kaempferol could efficiently prevent tumor progression of GBC in the xenograft in vivo.. Our results demonstrated that kaempferol suppressed GBC progression through activation of the CDK4/CDK6/cyclin D1 signaling pathway, suggesting that it might be a potential anti-tumor agent for clinical treatment of GBC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; DNA Damage; Drug Screening Assays, Antitumor; Female; Gallbladder Neoplasms; Humans; Kaempferols; Mice; Mice, Inbred BALB C; Neoplasms, Experimental; Tumor Cells, Cultured

Functional activation of beta-catenin/T-cell factor (Tcf) signaling has been implicated in human carcinogenesis. We identified the inhibitory effect of various polyphenolic flavonoid compounds against beta-catenin/Tcf signaling in beta-catenin-activated cells. Genistein, kaempferol, isorhamnentin, and baicalein inhibited the transcriptional activity of beta-catenin/Tcf in HEK293 cells transiently transfected with a constitutively active mutant beta-catenin gene. To investigate the inhibitory mechanism, electrophoresis mobility shift assay, immunoprecipitation, and Western blot experiments were performed. The shift assay showed that the binding of Tcf complexes with its specific DNA-binding sites was suppressed by four kinds of flavonoids. Immunoprecipitation analysis also showed that the binding of beta-catenin to Tcf-4 was also disrupted by these flavonoids. Western blot analysis showed a decreased level of beta-catenin in nucleus caused by genistein. Genistein also decreased phosphorylation of Akt and GSK3 beta. Taken together, these results suggest that the polyphenolic flavonoids genistein, kaempferol, isorhamnentin, and baicalein are negative regulators of beta-catenin/Tcf signaling and their inhibitory mechanism is related to the decreased binding of beta-catenin/Tcf complexes to consensus DNA.

Topics: Axin Protein; beta Catenin; Blotting, Western; Cell Line; Cell Line, Tumor; Cyclin D1; Cytoskeletal Proteins; Flavanones; Flavonoids; Flavonols; Gene Expression; Genistein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Kaempferols; Mutation; Phosphorylation; Protein Binding; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Quercetin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; TCF Transcription Factors

Estrogens are mitogenic for estrogen receptor (ER)-positive breast cancer cells. Current treatment of ER-positive breast tumors is directed towards interruption of estrogen activity. We report that treatment of ER-positive breast cancer cells with kaempferol resulted in a time- and dose-dependent decrease in cell number. The concentration required to produce 50% growth inhibition at 48 h was approximately 35.0 and 70.0 microM for ER-positive and ER-negative breast cancer cells, respectively. For MCF-7 cells, a reduction in the ER-alpha mRNA equivalent to 50, 12, 10% of controls was observed 24 h after treatment with 17.5, 35.0, and 70.0 microM of kaempferol, respectively. Concomitantly, these treatments led to a 58, 80, and 85% decrease in ER-alpha protein. The inhibitory effect of kaempferol on ER-alpha levels was seen as early as 6 h post-treatment. Kaempferol treatment also led in a dose-dependent decrease in the expression of progesterone receptor (PgR), cyclin D1, and insulin receptor substrate 1 (IRS-1). Immunocytochemical study revealed that ER-alpha protein in kaempferol-treated MCF-7 cells formed an aggregation in the nuclei. Kaempferol also induced degradation of ER-alpha by a different pathway than that were observed for the antiestrogen ICI 182,780 and estradiol. Estradiol-induced MCF-7 cell proliferation and expression of the estrogen-responsive-element-reporter gene activity were abolished in cells co-treated with kaempferol. These findings suggest that modulation of ER-alpha expression and function by kaempferol may be, in part, responsible for its anti-proliferative effects seen in in vitro.

Topics: Blotting, Northern; Blotting, Western; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cyclin D1; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Female; Fulvestrant; Humans; Immunohistochemistry; Insulin Receptor Substrate Proteins; Kaempferols; Phosphoproteins; Receptors, Estrogen; Receptors, Progesterone; Time Factors; Transfection