title: ICER evokes Dusp1-p38 pathway enhancing chemotherapy sensitivity in myeloid leukemia.
abstract: OBJECTIVE
  The inducible cyclic adenosine monophosphate (cAMP) early repressor (ICER) is found downregulated in acute myeloid leukemia (AML), failing to control cAMP response element binding protein (CREB) transcriptional activity, recently demonstrated to mediate AML progression. We aimed to characterize ICER's role in drug sensitivity by treating myeloid cell lines and primary AML with chemotherapics.
  
  
  METHODS
  The effects on CREB target genes induced by ICER restoration and drug treatment were studied by quantitative real-time PCR (qRT-PCR) and western blot. Cell cycle and apoptosis analysis were performed. Possible ICER-evoked pathways were investigated in vitro. The mechanism involved in enhanced drug sensitivity was described in primary AML cultures by silencing ICER main target genes.
  
  
  RESULTS
  AML cell lines reduced cell growth and enhanced apoptotic behavior after chemotherapy treatment if ICER was expressed. A significantly lowered expression of CREB target genes involved in cell cycle control (CyA1, B1, D1), and in the mitogen-activated protein kinase signaling pathway (ERK, AKT, DUSP1/4), was found after Etoposide treatment. The dual-specificity phosphatases DUSP1 and DUSP4, directly repressed by ICER, activated the p38 pathway, which triggered enhanced caspase-dependent apoptosis. The silencing of DUSP1/4 in HL60 confirmed the same enhanced drug sensitivity induced by ICER. Primary AML cultures, silenced for DUSP1 as well as restored of ICER expression, showed DUSP1 downregulation and p38 activation.
  
  
  CONCLUSIONS
  ICER mediates chemotherapy anticancer activity through DUSP1-p38 pathway activation and drives the cell program from survival to apoptosis. ICER restoration or DUSP1 inhibition might be possible strategies to sensitize AML cancer cells to conventional chemotherapy and to inhibit tumor growth.
authors.affiliation: Department of Pediatrics, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy. martina.pigazzi@unipd.it
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
authors.forename: Elena
authors.initials: E
authors.lastname: Manara
authors.forename: Alessandra
authors.initials: A
authors.lastname: Beghin
authors.forename: Emma
authors.initials: E
authors.lastname: Baron
authors.forename: Claudia
authors.initials: C
authors.lastname: Tregnago
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
mesh_terms: D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000502:physiology*; D054637:Dual-Specificity Phosphatases / Q000235:genetics; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics; D034622:RNA Interference; D011994:Recombinant Proteins / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; C497410:CREM protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D051786:Cyclic AMP Response Element Modulator; D005047:Etoposide; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C517019:DUSP1 protein, human; C490583:DUSP4 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D019311:Staurosporine