dorsomorphin and Liver-Neoplasms

Several of the different bone morphogenetic proteins (BMPs) are involved in development and progression of specific tumors. For hepatocellular carcinoma (HCC) only BMP4 and BMP6 are described to be important for carcinogenesis. However, up to now neither the influence of other BMPs on tumor progression, nor the responsible signaling pathways to mediate target gene expression in HCC are known. In order to characterize BMP expression pattern in HCC cell lines, we performed RT-PCR analysis and revealed enhanced expression levels of several BMPs (BMP4, 6, 7, 8, 9, 10, 11, 13 and 15) in HCC. Thus, we treated HCC cells with the general BMP inhibitors chordin and noggin to determine the functional relevance of BMP overexpression and observed decreased migration and invasion of HCC cells. A cDNA microarray of noggin treated HCC cells was performed to analyze downstream targets of BMPs mediating these oncogenic functions. Subsequent analysis identified collagen XVI as 'Smad signaling specific' and nidogen-2 as 'MAPK/ERK signaling specific' BMP-target genes. To examine which signaling pathway is mainly responsible for the oncogenic role of BMPs in HCC, we treated HCC cells with dorsomorphin to determine the influence of BMP activated Smad signaling. Interestingly, also migratory and invasive behavior of dorsomorphin treated HCC cells was diminished. In summary, our findings demonstrate enhanced expression levels of several BMPs in HCC supporting enhanced migratory and invasive phenotype of HCC cells mainly via activation of Smad signaling.

Topics: Bone Morphogenetic Proteins; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cells, Cultured; DNA, Complementary; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Liver Neoplasms; Neoplasm Invasiveness; Oligonucleotide Array Sequence Analysis; Phenotype; Pyrazoles; Pyrimidines; RNA, Messenger; RNA, Neoplasm; Signal Transduction; Smad Proteins

Luteolin, a plant-derived flavonoid, is thought to inhibit tumor growth. However, the precise molecular mechanisms by which luteolin inhibits cancer cell growth remain unclear. In the present study, we evaluated the role of AMP-activated protein kinase (AMPK) in the inhibition of cancer cell growth by luteolin in HepG2 hepatocarcinoma cells. AMPK is a metabolic sensor and may prevent carcinogenesis via modulation of signaling networks. We found that luteolin strongly induced cell death in HepG2 cells and dramatically reduced the tumor volume in a tumor xenograft model; both effects were accompanied by AMPK activation by luteolin. Luteolin also had a strong inhibitory effect on nuclear factor (NF)-κB. To determine the relationship between AMPK and NF-κB signaling, we used Compound C, a pharmacological AMPK inhibitor, and a dominant-negative form of AMPK. Our results indicated that inhibition of AMPK activity restored luteolin-inhibited NF-κB DNA-binding activity. These results suggest that AMPK activity is critical for the inhibition of cancer cell growth, possibly via modulation of NF-κB activity. We also showed that luteolin treatment causes the release of reactive oxygen species (ROS) and that these intracellular ROS in turn mediate AMPK-NF-κB signaling in HepG2 hepatocarcinoma cells. In conclusion, we propose that AMPK is a novel regulator of NF-κB in luteolin-induced cancer cell death. Furthermore, our results suggest that AMPK is an attractive target for cancer prevention by flavonoids.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Luteolin; Mice; Neoplasms; NF-kappa B; Pyrazoles; Pyrimidines; Reactive Oxygen Species; Signal Transduction; Xenograft Model Antitumor Assays