Up-regulation of HO-1 promotes resistance of B-cell acute lymphocytic leukemia cells to HDAC4/5 inhibitor LMK-235 via the Smad7 pathway

  • Life Sci. 2018 Aug 15;207:386-394. doi: 10.1016/j.lfs.2018.06.004.
Yongling Guo  1 ,  Qin Fang  2 ,  Dan Ma  3 ,  Kunling Yu  2 ,  Bingqing Cheng  2 ,  Sishi Tang  4 ,  Tingting Lu  4 ,  Weili Wang  2 ,  Jishi Wang  5
Affiliations
  • 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: [email protected].
PMID: 29886060 DOI: 10.1016/j.lfs.2018.06.004
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.

Keywords
Apoptosis; B-ALL; HO-1; LMK-235; Prognosis; Smad7.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18998
    LMK-235
    99.61%, HDAC4/5 Inhibitor
    target: HDAC
    Research Areas: Cancer