title: All-trans retinoic acid arrests cell cycle in leukemic bone marrow stromal cells by increasing intercellular communication through connexin 43-mediated gap junction.
abstract: BACKGROUND
  Gap junctional intercellular communication (GJIC) is typically decreased in malignant tumors. Gap junction is not presented between hematopoietic cells but occurred in bone marrow stromal cells (BMSCs). Connexin 43 (Cx43) is the major gap junction (GJ) protein; our previous study revealed that Cx43 expression and GJIC were decreased in acute leukemic BMSCs. All-trans retinoic acid (ATRA) increases GJIC in a variety of cancer cells and has been used to treat acute promyelocytic leukemia, but the effects of ATRA on leukemic BMSCs is unknown. In this study, we evaluated the potential effects of ATRA on cell cycle, proliferation, and apoptosis of leukemic BMSCs. Effects of ATRA on Cx43 expression and GJIC were also examined.
  
  
  METHODS
  Human BMSCs obtained from 25 patients with primary acute leukemia, and 10 normal healthy donors were cultured. Effects of ATRA on cell cycle, cell proliferation, and apoptosis were examined with or without co-treatment with amphotericin-B. Cx43 expression was examined at both the mRNA and protein expression levels. GJIC was examined by using a dye transfer assay and measuring the rate of fluorescence recovery after photobleaching (FRAP).
  
  
  RESULTS
  ATRA arrested the cell cycle progression, inhibited cell growth, and increased apoptosis in leukemic BMSCs. Both Cx43 expression and GJIC function were increased by ATRA treatment. Most of the observed effects mediated by ATRA were abolished by amphotericin-B pretreatment.
  
  
  CONCLUSIONS
  ATRA arrests cell cycle progression in leukemic BMSCs, likely due to upregulating Cx43 expression and enhancing GJIC function.
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. yl749@foxmail.com.|Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. yl749@foxmail.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. qiqi105@sina.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. chenxuelian9@gmail.com.
authors.forename: Xue-Lian
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. xyzysj102@163.com.
authors.forename: Shi-Jie
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. gaolei7765@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. gaotiantiantiger@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. chengzhang2006@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. l135940@aliyun.com.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Li
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. cherry_xiangxixi@163.com.
authors.forename: Xi-Xi
authors.initials: XX
authors.lastname: Xiang
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. wankai1111@163.com.
authors.forename: Kai
authors.initials: K
authors.lastname: Wan
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. xhchen888@aliyun.com.
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Chen
authors.affiliation: Department of Hematology, Xinqiao Hospital, the Third Military Medical University, Xinqiao Street, Chongqing, 400037, China. zhangxxi@sina.com.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. jzhong@usc.edu.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Zhong
mesh_terms: D000208:Acute Disease; D000328:Adult; D000666:Amphotericin B / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; C500216:GJA1 protein, human; D014212:Tretinoin; D000666:Amphotericin B