cyclin-d1 and decursin

Topics: Angelica; Antineoplastic Agents; Apoptosis; Benzopyrans; Butyrates; Caspase 3; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Cyclin D1; Cyclin-Dependent Kinase 4; G1 Phase Cell Cycle Checkpoints; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; p38 Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Phosphorylation; Plant Extracts; Plant Roots

The peptidyl-prolyl cis/trans isomerase Pin1 is overexpressed in a wide variety of cancer cells and thus considered as an important target molecule for cancer therapy. This study demonstrates that decursin, a bioactive compound from Angelica gigas, exert the anti-cancer effect against breast cancer cells via regulation of Pin1 and its related signaling molecules. We observed that decursin induced G1 arrest with decrease in cyclin D1 level in Pin1-expressing breast cancer cells MDA-MB-231, but not Pin1-non-expressing breast cancer cells MDA-MB-157. In addition, decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Further, we found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, our current study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1 protein.

Topics: Angelica; Benzopyrans; Breast Neoplasms; Butyrates; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin D1; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase; Tumor Suppressor Protein p53

Recent reports have indicated that decursin can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this experiment, we investigated how decursin could potentiate the cytotoxic effects of bortezomib in human multiple myeloma cells. We found that decursin inhibited cell viability in U266, MM.1S and ARH77 cells, but not in peripheral blood mononuclear cells (PBMC). Decursin-induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. This correlated with the down-regulating of cyclin D1, bcl-2, bcl-xL, survivin, and the vascular endothelial growth factor (VEGF), which are all regulated by the activation of signal transducers and the activator of transcription 3 (STAT3). Indeed, decursin inhibited constitutive STAT3 activation through inhibition of the activation of Janus-activated kinase 2 (JAK2) in U266 cells. In addition, decursin inhibited interleukin-6-inducible STAT3 activation in a time-dependent manner in MM.1S cells. Interestingly, decursin significantly potentiated the apoptotic effects of bortezomib in U266 cells. These effects of decursin were correlated with the suppression of constitutive STAT3 activation in U266 cells. Overall, these results suggest that decursin is a novel blocker of STAT3 activation and it may be a potential candidate for overcoming chemo-resistance through suppression of this signaling.

Topics: Apoptosis; Benzopyrans; Boronic Acids; Bortezomib; Butyrates; Caspase 3; Cell Line, Tumor; Cyclin D1; DNA; G1 Phase; Humans; Interleukin-6; Janus Kinase 2; Multiple Myeloma; Phosphorylation; Pyrazines; Signal Transduction; STAT3 Transcription Factor

Estrogen and estrogen receptor (ER)-mediated signaling are crucial for the etiology and progression of human breast cancer. Attenuating ER activities by natural products is a promising strategy to decrease breast cancer risk. We recently discovered that the pyranocoumarin compound decursin and its isomer decursinol angelate (DA) have potent novel antiandrogen receptor signaling activities. Because the ER and the androgen receptor belong to the steroid receptor superfamily, we examined whether these compounds affected ER expression and signaling in breast cancer cells.. We treated estrogen-dependent MCF-7 and estrogen-independent MDA MB-231 human breast cancer cells with decursin and DA, and examined cell growth, apoptosis, and ERalpha and ERbeta expression in both cell lines - and, in particular, estrogen-stimulated signaling in the MCF-7 cells. We compared these compounds with decursinol to determine their structure-activity relationship.. Decursin and DA exerted growth inhibitory effects on MCF-7 cells through G1 arrest and caspase-mediated apoptosis. These compounds decreased ERalpha in MCF-7 cells at both mRNA and protein levels, and suppressed estrogen-stimulated genes. Decursin and the pure antiestrogen Faslodex exerted an additive growth inhibitory effect on MCF-7 cells. In MDA MB-231 cells, these compounds induced cell-cycle arrests in the G1 and G2 phases as well as inducing apoptosis, accompanied by an increased expression of ERbeta. In contrast, decursinol, which lacks the side chain of decursin and DA, did not have these cellular and molecular activities at comparable concentrations.. The side chain of decursin and DA is crucial for their anti-ER signaling and breast cancer growth inhibitory activities. These data provide mechanistic rationales for validating the chemopreventive and therapeutic efficacy of decursin and its derivatives in preclinical animal models of breast cancer.

Topics: Antineoplastic Agents; Apoptosis; Benzopyrans; Breast Neoplasms; Butyrates; Caspases; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cytosol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Protein Kinase C; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Up-Regulation