oxalylglycine and Prostatic-Neoplasms

Hypoxia inducible factor 1 alpha (HIF-1α) is frequently over-expressed in the numerous types of cancer and plays an important role in angiogenesis. In the present study, the inhibitory mechanism of rhapontigenin isolated from Vitis coignetiae was investigated on HIF-1α stability and angiogenesis in human prostate cancer PC-3 cells. Rhapontigenin significantly suppressed HIF-1α accumulation at protein level but not at mRNA level in PC-3 cells under hypoxia. Also, rhapontigenin suppressed hypoxia-induced HIF-1α activation in various cancer cells, such as colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF-7), fibrosarcoma (HT-1080) and prostate carcinoma (LNCaP). Interestingly, rhapontigenin had more potency in inhibition of hypoxia-induced HIF-1α expression than that of resveratrol, a known HIF-1α inhibitor. In addition, rhapontigenin promoted hypoxia-induced HIF-1α degradation and cycloheximide (CHX) blocked protein synthesis. A prolyl hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) is usually utilized to examine whether prolyl hydroxylation is involved in inhibition of HIF-1α accumulation. Here, DMOG recovered HIF-1α accumulation inhibited by rhapontigenin. Immunoprecipitation assay also revealed that rhapotigenin enhanced the binding of hydroxylated HIF-1α to von Hippel-Lindau (VHL) tumor suppressor protein. Furthermore, rhapontigenin reduced vascular endothelial growth factor (VEGF) secretion in hypoxic PC-3 cells as well as suppressed tube formation in human umbilical vein endothelial cells (HUVECs) treated by the conditioned media of hypoxic PC-3 cells. However, anti-angiogenic effect of rhapontigenin in hypoxic PC-3 cells was reversed by DMOG. Taken together, these findings suggest that rhapontigenin inhibits HIF-1α accumulation and angiogenesis in PC-3 prostate cancer cells.

Topics: Amino Acids, Dicarboxylic; Angiogenesis Inhibitors; Carcinoma; Cell Hypoxia; Cell Line; Cell Line, Tumor; Culture Media, Conditioned; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Neoplasms; Neovascularization, Pathologic; Procollagen-Proline Dioxygenase; Prostatic Neoplasms; Protein Processing, Post-Translational; Stilbenes; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

Prostate-specific antigen (PSA) is a well-known marker for diagnosing and monitoring prostate cancer. Curcumin, a yellow curry pigment, has been reported to enhance androgen receptor (AR) degradation. We examined the effects of curcumin on increasing PSA expression by hypoxia and prolyl hydroxylase inhibitors, L-mimosine and dimethyloxalylglycine (DMOG), in human prostate carcinoma LNCaP cells.. The 3H-thymidine incorporation assay revealed that either L-mimosine or DMOG treatments attenuated cell proliferation. Immunoblot and enzyme-linked immunosorbent assays (ELISA) indicated that both L-mimosine and DMOG have an effect similar to hypoxia, which stabilized hypoxia-inducible factor-1α (HIF-1α) and induced PSA gene expression. The results of the immunoblot and transient gene expression assays indicated that induction of the PSA expression by hypoxia is both HIF-1α- and AR-dependent. Immunoblot assays revealed that a curcumin treatment (10 μM) decreased the protein abundance of AR but did not significantly affect the protein levels of HIF-1α and vascular endothelial growth factor, which were induced by hypoxia. ELISA and transient gene expression assays indicated that curcumin blocked the activation of L-mimosine or DMOG treatment on PSA expression.. These results indicate that curcumin blocked the enhanced effect of PSA expression by L-mimosine and DMOG that induce hypoxia condition.

Topics: Amino Acids, Dicarboxylic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Carcinoma; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Iron Chelating Agents; Male; Mimosine; Neoplasm Proteins; Procollagen-Proline Dioxygenase; Prostate-Specific Antigen; Prostatic Neoplasms; Recombinant Proteins