ki-8751 and Breast-Neoplasms

Vascular endothelial growth factor (VEGF), apart from its predominant roles in angiogenesis, can enhance cancer cell proliferation, but its mechanisms remain elusive. The purpose of the present study was therefore to identify how VEGF regulates cancer cell proliferation.. VEGF effects on cancer cell proliferation were investigated with the VEGF receptor 2 inhibitor, Ki8751, and the breast cancer cell lines, MCF-7 and MDA-MB-231, using flow cytometry, mass spectrometry, immunoblotting, and confocal microscopy. Data were analyzed using one-way analysis of variance followed by Tukey's multiple comparison test.. VEGF blockade by Ki8751 significantly reduced cancer cell proliferation, and enhanced breast cancer cell apoptosis. Mass spectrometric analyses revealed that Ki8751 treatment significantly upregulated the expression of mitochondrial proteins, suggesting the involvement of mitochondrial biogenesis. Confocal microscopy and flow cytometric analyses showed that Ki8751 treatment robustly increased the mitochondrial masses of both cancer cells, induced endomitosis, and arrested cancer cells in the high aneuploid phase. VEGFR2 knockdown by shRNAs showed similar effects to those of Ki8751, confirming the specificity of Ki8751 treatment. Enhanced mitochondrial biogenesis increased mitochondrial oxidative phosphorylation and stimulated reactive oxygen species (ROS) production, which induced cancer cell apoptosis. Furthermore, Ki8751 treatment downregulated the phosphorylation of Akt and PGC1α, and translocated PGC1α into the nucleus. The PGC1α alterations increased mitochondrial transcription factor A (TFAM) expression and subsequently increased mitochondrial biogenesis.. VEGF enhances cancer cell proliferation by decreasing Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis, ROS production, and cell apoptosis. These findings suggested the anticancer potential of Ki8751

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Humans; Mitochondria; Mitochondrial Proteins; Neovascularization, Pathologic; Organelle Biogenesis; Phenylurea Compounds; Quinolines; Signal Transduction; Transcription Factors; Vascular Endothelial Growth Factor Receptor-2

Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth.. Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors).. The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis.. Platelet releasate increases breast cancer cell proliferation through VEGF-integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.

Topics: Adult; Animals; Blood Platelets; Breast Neoplasms; Cell Proliferation; Endothelial Cells; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrins; Male; MCF-7 Cells; Mice; Mice, Nude; Middle Aged; Neovascularization, Pathologic; Oligopeptides; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Protein Kinase C; Quinolines; Receptor, PAR-1; Receptors, CXCR4; Receptors, Thrombin; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2