title: Arsenic trioxide inhibits the Hedgehog pathway which is aberrantly activated in acute promyelocytic leukemia.
abstract: OBJECTIVE
  Dysregulated Hedgehog (Hh) signaling has been implicated in several human malignancies. Hh signaling inhibitors are predicted to have a minimal effect when the Smoothened receptor is mutated. Implications that Gli proteins are molecular targets of arsenic trioxide (ATO) action prompted us to investigate the expression of Hh signaling in acute promyelocytic leukemia (APL) and the influence of ATO on the Hh signaling pathway in APL.
  
  
  METHODS
  Quantitative real-time reverse transcription polymerase chain reaction and Western blot were employed to analyze the expression of Hh pathway components and the influence of ATO on the Hh signaling pathway in APL.
  
  
  RESULTS
  The expression of Hh pathway components was significantly upregulated in APL. In newly diagnosed APL patients, Gli2 expression was significantly positively correlated with Gli1 (R = 0.57, p < 0.001) and Smo (R = 0.56, p < 0.001) and the expression of Hh pathway components was significantly higher in the high WBC group (p < 0.05). ATO can significantly downregulate the expression of Hh pathway components in vitro and in vivo (p < 0.05).
  
  
  CONCLUSIONS
  The Hh pathway is aberrantly activated in APL and associated with a bad prognostic factor. ATO can effectively inhibit the expression of the Hh pathway. The obtained data give the first clinical evidence for the application of ATO in tumors exhibiting an aberrantly activated Hh pathway.
authors.affiliation: Health Ministry Key Lab of Cell Transplantation, Heilongjiang Institute of Hematology and Oncology, First Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Dongguang
authors.initials: D
authors.lastname: Yang
authors.forename: Fenglin
authors.initials: F
authors.lastname: Cao
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Ye
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.forename: Hongling
authors.initials: H
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000096:biosynthesis; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: D001152:Arsenicals; C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D010087:Oxides; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000077237:Arsenic Trioxide