title: Suppression of survivin induced by a BCR-ABL/JAK2/STAT3 pathway sensitizes imatinib-resistant CML cells to different cytotoxic drugs.
abstract: The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) displays exclusive cytoplasmic localization and constitutive tyrosine kinase activity leading to the activation of different pathways that favor cell proliferation and survival. BCR-ABL induces survivin expression at both the mRNA and protein level, thus inhibiting the apoptotic machinery of CML cells and contributing to the expansion of the leukemic clone. We report that, in human CML cell lines, BCR-ABL-mediated upregulation of survivin involves the JAK2/STAT3 pathway since silencing of either protein caused a consistent reduction in survivin expression. Cell lines unresponsive to imatinib mesylate (IM) because of BCR-ABL gene amplification were not resensitized to the drug after survivin downregulation. However, cells insensitive to IM because of point mutations in the BCR-ABL kinase domain were highly responsive to hydroxyurea (HU) after survivin silencing. To address the possible clinical applications of our results, we used shepherdin, a cell-permeable peptidomimetic compound that downregulates survivin expression by preventing its interaction with Hsp90. Incubation with shepherdin of immortalized cell lines both sensitive and resistant to IM enhanced cell death induced by HU and doxorubicin. Similarly, the combination of shepherdin with first- and second-generation tyrosine kinase inhibitors reduced the colony-forming potential of human progenitors derived from both patients with IM-sensitive and IM-resistant CML. These results suggest that strategies aimed at reducing survivin levels may represent a potential therapeutic option for patients with CML unresponsive to IM.
authors.affiliation: Department of Clinical and Molecular Bio-Medicine, University of Catania, Catania, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Stella
authors.forename: Elena
authors.initials: E
authors.lastname: Tirrò
authors.forename: Enrico
authors.initials: E
authors.lastname: Conte
authors.forename: Fabio
authors.initials: F
authors.lastname: Stagno
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Raimondo
authors.forename: Livia
authors.initials: L
authors.lastname: Manzella
authors.forename: Paolo
authors.initials: P
authors.lastname: Vigneri
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016313:Genes, abl / Q000235:genetics*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D010879:Piperazines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D004317:Doxorubicin; D000068877:Imatinib Mesylate; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D006918:Hydroxyurea