PURPOSE: 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.
PURPOSE: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 humanchronic 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: Mark A Feitelson; Alla Arzumanyan; Rob J Kulathinal; Stacy W Blain; Randall F Holcombe; Jamal Mahajna; Maria Marino; Maria L Martinez-Chantar; Roman Nawroth; Isidro Sanchez-Garcia; Dipali Sharma; Neeraj K Saxena; Neetu Singh; Panagiotis J Vlachostergios; Shanchun Guo; Kanya Honoki; Hiromasa Fujii; Alexandros G Georgakilas; Alan Bilsland; Amedeo Amedei; Elena Niccolai; Amr Amin; S Salman Ashraf; Chandra S Boosani; Gunjan Guha; Maria Rosa Ciriolo; Katia Aquilano; Sophie Chen; Sulma I Mohammed; Asfar S Azmi; Dipita Bhakta; Dorota Halicka; W Nicol Keith; Somaira Nowsheen Journal: Semin Cancer Biol Date: 2015-04-17 Impact factor: 15.707