title: The STAT3 inhibitor WP1066 reverses the resistance of chronic lymphocytic leukemia cells to histone deacetylase inhibitors induced by interleukin-6.
abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine produced by a variety of cell types, including fibroblasts, endothelial cells, lymphocytes, and bone marrow stromal cells (BMSCs). Levels of IL-6 are increased in serum of CLL patients and correlated with adverse clinical features and short survival. In our study, we observed that IL-6 induced the resistance of CLL cells to pan-histone deacetylase (HDAC) inhibitors vorinostat (SAHA) and panobinostat (LBH589). Furthermore, low concentrations of SAHA and LBH589 enhanced the activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway induced by IL-6 in CLL cells. All of these effects were blocked by the STAT3-selective inhibitor, WP1066. Meanwhile, WP1066 decreased the expressions of Mcl-1 and Bcl-xL protein induced by IL-6 with or without low concentrations of HDAC inhibitors. Co-culture of CLL cells with BMSCs could also facilitate the activation of STAT3 and protected CLL cells from apoptosis when treated with HDAC inhibitors, and this cytoprotection was reversed by WP1066. The present study indicated that IL-6 or co-culture with BMSCs prevented HDAC inhibitor-induced apoptosis of CLL cells. This prevention was mediated by activation of the STAT3 signaling pathway. Moreover, WP1066 reversed the resistance of CLL cells to SAHA and LBH589 induced by either IL-6 or co-culture with BMSCs. Our findings suggest that targeting the STAT3 pathway may be a novel way to improve the efficacy of the HDAC inhibitor in CLL patients by overcoming antiapoptotic signaling of the microenvironment.
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Kang
authors: K
authors: Lu
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Xiao-sheng
authors: XS
authors: Fang
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Li-li
authors: LL
authors: Feng
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Yu-jie
authors: YJ
authors: Jiang
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Xiang-xiang
authors: XX
authors: Zhou
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Xin
authors: X
authors: Liu
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Pei-pei
authors: PP
authors: Li
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Na
authors: N
authors: Chen
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Mei
authors: M
authors: Ding
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Na
authors: N
authors: Wang
authors: Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China.
authors: Jie
authors: J
authors: Zhang
authors: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, China; Institute of Diagnostics, Shandong University, Jinan, Shandong 250012, China. Electronic address: xinw007@126.com.
authors: Xin
authors: X
authors: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D000077767:Panobinostat; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*; D000077337:Vorinostat; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508600:IL6 protein, human; D007211:Indoles; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C519885:WP1066; D051020:bcl-X Protein; D000077337:Vorinostat; D000077767:Panobinostat
keywords: Apoptosis; Chronic lymphocytic leukemia; Histone deacetylase; Interleukin-6; STAT3