title: Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells.
abstract: BACKGROUND
  Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells.
  
  
  RESULTS
  Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control.
  
  
  CONCLUSIONS
  These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells.
authors.affiliation: Clinical Trial Institute, Dankook University, Chenan, South Korea.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Wonil
authors.initials: W
authors.lastname: Koh
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Kim
authors.initials: K
authors.lastname: Sung-Hoon
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000187:drug effects / Q000378:metabolism; D000077278:RNA, Mitochondrial; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000077278:RNA, Mitochondrial; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012313:RNA; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; C036071:ergosterol-5,8-peroxide; D004875:Ergosterol