title: Apigenin-induced apoptosis of leukemia cells is mediated by a bimodal and differentially regulated residue-specific phosphorylation of heat-shock protein-27.
abstract: Apigenin, a natural plant flavonoid with antiproliferative activity, is emerging as a promising compound for cancer prevention and therapy, but its mechanism of action remains unclear. High expression of the small heat-shock protein-27 (Hsp27) in leukemia contributes to the resistance of these cells to cancer treatments. Changes in Hsp27 phosphorylation have been associated with heat and metabolic stress, but its role in flavonoid anticancer activity has not been investigated. In this study, we examined the effect of apigenin in the regulation of Hsp27 on leukemia. We showed that apigenin does not affect Hsp27 expression but induces a bimodal phosphorylation on Ser78 and Ser82. The phosphorylation at early times was regulated by p38. At later times, Hsp27 phosphorylation was dependent on p38 activity and for some residues on PKCδ. Silencing of p38 expression reduced apigenin-induced phosphorylation on Ser15, Ser78, and Ser82, whereas silencing of PKCδ expression reduced the phosphorylation on Ser15 and Ser82 without affecting Ser78. In addition, we found that apigenin-induced PKCδ activity is mediated by p38. We also showed that the phosphorylation of Hsp27 significantly increased the susceptibility of leukemia cells to apigenin-induced apoptosis. Together, these results identify a complex signaling network regulating the cytotoxic effect of apigenin through Hsp27 phosphorylation.
authors.affiliation: Department of Molecular Genetics, Division of Pulmonary and Critical Care, The Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Gonzalez-Mejia
authors.forename: O H
authors.initials: OH
authors.lastname: Voss
authors.forename: E J
authors.initials: EJ
authors.lastname: Murnan
authors.forename: A I
authors.initials: AI
authors.lastname: Doseff
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000596:Amino Acids; D055551:HSP27 Heat-Shock Proteins; D047310:Apigenin; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases