title: Sonic hedgehog signaling regulates Bcr-Abl expression in human chronic myeloid leukemia cells.
abstract: OBJECTIVE
  Bcr-Abl fusion protein activates tyrosine kinase, resulting in the proliferation of leukemia cells, especially chronic myeloid leukemia (CML) cells. Imatinib (IM) effectively targets Bcr-Abl tyrosine kinase, but development of resistance to IM occurs with varying frequency.
  
  
  METHODS
  Elucidation of the common regulatory pathway upstream of Bcr-Abl in IM-sensitive and IM-resistant CML cells is important for developing novel therapeutics against CML.
  
  
  RESULTS
  This study demonstrated that IM preferentially inhibited the viability and Bcr-Abl expression in IM-sensitive K562 (K562) cells, but not in Bcr-Abl overexpressing IM-resistant K562 (K562R) cells. Both K562 and K562R cells expressed Shh preproprotein, cleaved Shh C-terminal and N-terminal peptides, as well as mRNA level of major Shh signaling molecules, including sonic hedgehog (Shh), patched (PTCH), smoothened (Smo) and Gli-1. Moreover, Gli-1 translocation into nucleus was evident in these two cell lines, suggesting that both K562 and K562R cells possess activated and major components of the Shh signaling pathway. Silencing of Gli-1 by interference RNA was accompanied by inhibition of Bcr-Abl protein expression. Pharmacological suppression of Bcr-Abl expression was restored by the Smo agonist purmorpharmine. Treatment of Shh peptide in both K562 and K562R cells not only increased Shh and Gli-1 expression, but also up-regulated Bcr-Abl expression. Resveratrol, a known Bcr-Abl inhibitor, reduced Gli-1 activation and inhibited the viability of CML cells.
  
  
  CONCLUSIONS
  Shh signaling may regulate Bcr-Abl expression in human chronic myeloid leukemia cells. Novel compounds inhibiting both Shh signaling and Bcr-Abl expression, such as resveratrol, may have potential to be effective agents against CML independent of IM resistance.
authors.affiliation: Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan.
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Liao
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Su
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Zheng
authors.forename: Chang
authors.initials: C
authors.lastname: Jhih Cai
authors.forename: Ming-Hung
authors.initials: MH
authors.lastname: Hou
authors.forename: K S Clifford
authors.initials: KS
authors.lastname: Chao
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D053823:Hedgehog Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C509239:SHH protein, human; D013267:Stilbenes; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000077185:Resveratrol