Yongling Guo1, Qin Fang2, Dan Ma3, Kunling Yu2, Bingqing Cheng2, Sishi Tang4, Tingting Lu4, Weili Wang2, Jishi Wang5. 1. School of Clinical Medicine, Guizhou Medical University, Guiyang, China; Department of Hematology, Guihang Guiyang Hospital, Guiyang, China. 2. College of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, China. 3. Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, China. 4. School of Clinical Medicine, Guizhou Medical University, Guiyang, China. 5. Key Laboratory of Hematological Disease Diagnostic Treat Centre of Guizhou Province, Guiyang, China. Electronic address: wangjishi9646@163.com.
Abstract
PURPOSE: HDAC4/5 and Smad7 are potential therapeutic targets for the onset and progression of B-cell acute lymphocytic leukemia (B-ALL) and indices for clinical prognosis. In contrast, HO-1 (heat shock protein 32) plays a key role in protecting tumor cells from apoptosis. METHODS: HDAC4/5, HO-1 and Smad7 expressions in 34 newly diagnosed B-ALL cases were detected by real-time PCR and Western blot. Lentivirus and small interference RNA were used to transfect B-ALL cells. The expression of Smad7 was detected after treatment with LMK-235 or Hemin and ZnPP. Apoptosis and proliferation were evaluated by flow cytometry, CCK-8 assay and Western blot. RESULTS: HDAC4/5 was overexpressed in B-ALL patients with high HO-1 levels. Increasing the concentration of HDAC4/5 inhibitor LMK-235 induced the decrease of Smad7 and HO-1 expressions and the apoptosis of B-ALL cells by suppressing the phosphorylation of AKT (Protein kinase B). Up-regulating HO-1 alleviated the decrease of Smad7 expression and enhanced B-ALL resistance to LMK-235 by activating p-AKT which reduced the apoptosis of B-ALL cells and influenced the survival of leukemia patients. Silencing Smad7 also augmented the apoptosis rate of B-ALL cells by suppressing p-AKT. CONCLUSION: HO-1 played a key role in protecting tumor cells from apoptosis, and HDAC4/5 were related with the apoptosis of B-ALL cells. LMK-235 may be able to improve the poor survival of leukemia patients.
PURPOSE:HDAC4/5 and Smad7 are potential therapeutic targets for the onset and progression of B-cell acute lymphocytic leukemia (B-ALL) and indices for clinical prognosis. In contrast, HO-1 (heat shock protein 32) plays a key role in protecting tumor cells from apoptosis. METHODS:HDAC4/5, HO-1 and Smad7 expressions in 34 newly diagnosed B-ALL cases were detected by real-time PCR and Western blot. Lentivirus and small interference RNA were used to transfect B-ALL cells. The expression of Smad7 was detected after treatment with LMK-235 or Hemin and ZnPP. Apoptosis and proliferation were evaluated by flow cytometry, CCK-8 assay and Western blot. RESULTS:HDAC4/5 was overexpressed in B-ALL patients with high HO-1 levels. Increasing the concentration of HDAC4/5 inhibitor LMK-235 induced the decrease of Smad7 and HO-1 expressions and the apoptosis of B-ALL cells by suppressing the phosphorylation of AKT (Protein kinase B). Up-regulating HO-1 alleviated the decrease of Smad7 expression and enhanced B-ALL resistance to LMK-235 by activating p-AKT which reduced the apoptosis of B-ALL cells and influenced the survival of leukemiapatients. Silencing Smad7 also augmented the apoptosis rate of B-ALL cells by suppressing p-AKT. CONCLUSION:HO-1 played a key role in protecting tumor cells from apoptosis, and HDAC4/5 were related with the apoptosis of B-ALL cells. LMK-235 may be able to improve the poor survival of leukemiapatients.
Authors: Julia Wanek; Martin Gaisberger; Marlena Beyreis; Christian Mayr; Katharina Helm; Florian Primavesi; Tarkan Jäger; Pietro Di Fazio; Martin Jakab; Andrej Wagner; Daniel Neureiter; Tobias Kiesslich Journal: Int J Mol Sci Date: 2018-10-12 Impact factor: 5.923