title: Inhibition of STAT3-interacting protein 1 (STATIP1) promotes STAT3 transcriptional up-regulation and imatinib mesylate resistance in the chronic myeloid leukemia.
abstract: BACKGROUND
  Signal transducer and activator of transcription 3 (STAT3) is an important transcriptional factor frequently associated with the proliferation and survival of a large number of distinct cancer types. However, the signaling pathways and mechanisms that regulate STAT3 activation remain to be elucidated.
  
  
  METHODS
  In this study we took advantage of existing cellular models for chronic myeloid leukemia resistance, western blot, in vitro signaling, real time PCR, flow cytometry approaches for cell cycle and apoptosis evaluation and siRNA assay in order to investigate the possible relationship between STATIP1, STAT3 and CML resistance.
  
  
  RESULTS
  Here, we report the characterization of STAT3 protein regulation by STAT3-interacting protein (STATIP1) in the leukemia cell line K562, which demonstrates constitutive BCR-ABL TK activity. K562 cells exhibit high levels of phosphorylated STAT3 accumulated in the nucleus and enhanced BCR-ABL-dependent STAT3 transcriptional activity. Moreover, we demonstrate that STATIP1 is not involved in either BCR-ABL or STAT3 signaling but that STATIP1 is involved in the down-regulation of STAT3 transcription levels; STATIP1-depleted K562 cells display increased proliferation and increased levels of the anti-apoptosis STAT3 target genes CCND1 and BCL-XL, respectively. Furthermore, we demonstrated that Lucena, an Imatinib (IM)-resistant cell line, exhibits lower STATIP1 mRNA levels and undergoes apoptosis/cell cycle arrest in response to STAT3 inhibition together with IM treatment. We provide evidence that STATIP1 siRNA could confer therapy resistance in the K562 cells. Moreover, analysis of CML patients showed an inverse expression of STAIP1 and STAT3 mRNA levels, ratifying that IM-resistant patients present low STATIP1/high STAT3 mRNA levels.
  
  
  CONCLUSIONS
  Our data suggest that STATIP1 may be a negative regulator of STAT3 and demonstrate its involvement in IM therapy resistance in CML.
authors.affiliation: Bone Marrow Transplantation Unit (CEMO), National Cancer Institute (INCA), Rio de Janeiro, Brazil. andre.mencalha@uerj.br.
authors.forename: André L
authors.initials: AL
authors.lastname: Mencalha
authors.forename: Stephany
authors.initials: S
authors.lastname: Corrêa
authors.forename: Daniela
authors.initials: D
authors.lastname: Salles
authors.forename: Bárbara
authors.initials: B
authors.lastname: Du Rocher
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Santiago
authors.forename: Eliana
authors.initials: E
authors.lastname: Abdelhay
mesh_terms: D000328:Adult; D000368:Aged; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D001549:Benzamides; C413649:ELP2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl