title: Ruthenium polypyridyl complex inhibits growth and metastasis of breast cancer cells by suppressing FAK signaling with enhancement of TRAIL-induced apoptosis.
abstract: Ruthenium-based complexes have emerged as promising antitumor and antimetastatic agents during the past decades. However, the limited understanding of the antimetastatic mechanisms of these agents is a roadblock to their clinical application. Herein, we reported that, RuPOP, a ruthenium polypyridyl complex with potent antitumor activity, was able to effectively inhibit growth and metastasis of MDA-MB-231 cells and synergistically enhance TRAIL-induced apoptosis. The selective intracellular uptake and cytotoxic effect of RuPOP was found associated with transferring receptor (TfR)-mediated endocytosis. Further investigation on intracellular mechanisms reveled that RuPOP notably suppressed FAK-mediated ERK and Akt activation. Pretreatment of cells with ERK inhibitor (U0126) and PI3K inhibitor (LY294002) significantly potentiated the inhibitory effect of RuPOP on cell growth, migration and invasion. Moreover, the alternation in the expression levels of metastatic regulatory proteins, including uPA, MMP-2/-9, and inhibition of VEGF secretion were also observed after RuPOP treatment. These results demonstrate the inhibitory effect of RuPOP on the growth and metastasis of cancer cells and the enhancement of TRAIL-induced apoptosis though suppression of FAK-mediated signaling. Furthermore, RuPOP exhibits the potential to be developed as a metal-based antimetastatic agent and chemosensitizer of TRAIL for the treatment of human metastatic cancers.
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, Jinan University, Guangzhou 510632, China.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004705:Endocytosis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D017975:Ruthenium Compounds / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D011990:Receptors, Transferrin; D017975:Ruthenium Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D042461:Vascular Endothelial Growth Factor A; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases