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.2015 Oct 7:8:110.
doi: 10.1186/s13045-015-0212-7.

All-trans retinoic acid arrests cell cycle in leukemic bone marrow stromal cells by increasing intercellular communication through connexin 43-mediated gap junction

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All-trans retinoic acid arrests cell cycle in leukemic bone marrow stromal cells by increasing intercellular communication through connexin 43-mediated gap junction

Yao Liu et al. J Hematol Oncol..

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.

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Figures

Fig. 1
Fig. 1
Effects of ATRA and amphotericin-B pretreatment on Cx43 mRNA level in leukemic BMSCs. Cx43 mRNA (normalized against β-actin) was 1.53 ± 0.14 in healthy controls (N = 10), 0.56 ± 0.07 leukemic BMSCs (N = 10) treated with DMSO, 1.21 ± 0.36 in leukemic BMSCs (N = 25) exposed to ATRA (10 uM), and 1.17 ± 0.196 in leukemic BMSCs exposed to ATRA + amphotericin-B. Data are presented as mean ± SD.Double asterisks indicateP < 0.01
Fig. 2
Fig. 2
Effects of ATRA and amphotericin-B pretreatment on Cx43 protein level in leukemic BMSCs.a Cx43 protein (normalized against β-actin) was 1.35 ± 0.17 in healthy controls (N = 10), 0.37 ± 0.02 in leukemic BMSCs (N = 25) treated with DMSO, 1.15 ± 0.03 in leukemic BMSCs exposed to ATRA (10 uM) (N = 25), and 1.07 ± 0.02 in leukemic BMSCs treated with both ATRA and amphotericin-B (N = 25);b relative normalization gray level of Cx43 Western blotting band in health controls, leukemic BMSCs, leukemic BMSCs + ATRA, leukemic BMSCs + ATRA + AB. Data are presented as mean ± SD.Double asterisks indicateP < 0.01
Fig. 3
Fig. 3
Effects of dye transfer between BMSCs by using laser confocal microscopy.a Leukemic BMSCs not exposed to ATRA;b leukemic BMSCs exposed to ATRA (10 M);c leukemic BMSCs treated with both ATRA and amphotericin-B. Scale bar = 50 um
Fig. 4
Fig. 4
FRAP assay in BMSCs.a Pre-photobleaching of leukemic BMSCs exposed to ATRA;b 1.5 s post-photobleaching of leukemic BMSCs exposed to ATRA;c 30 min post photobleaching of leukemic BMSCs exposed to ATRA.d–f Leukemic BMSCs without ATRA treatment (d pre-photobleaching of leukemic BMSCs without ATRA treatment;e 1.5 s post-photobleaching of leukemic BMSCs without ATRA treatment;f 30 min post photobleaching of leukemic BMSCs without ATRA treatment).g Effects of ATRA on fluorescence redistribution in leukemic BMSCs.h Effects of ATRA on GJIC in leukemic BMSCs.Arrow symbols photobleached cells. *p < 0.01 vs. leukemic BMSCs. Images were taken under a laser confocal microscope at ×400 magnification
Fig. 5
Fig. 5
Effects of ATRA on the cell viability of BMSCs (MTT assay). Cell viability was evaluated by MTT assay in leukemic BMSCs, leukemic BMSCs treated with ATRA, and leukemic BMSCs treated with both ATRA and amphotericin-B. Data are presented as mean ± SD.Single asterisk indicates significant difference (P < 0.05)
Fig. 6
Fig. 6
Effects of ATRA on the cell cycle (FCM assay). Cell cycle was examined with FCM assay in leukemic BMSCs, leukemic BMSCs treated with ATRA, and leukemic BMSCs treated with both ATRA and amphotericin-B. Data are presented as mean ± SD.Single asterisk indicates significant difference (P < 0.05)
Fig. 7
Fig. 7
Effects of ATRA on the apoptosis of BMSCs (FCM assay). Cell apoptosis was examined with FCM assay in leukemic BMSCs, leukemic BMSCs treated with ATRA, and leukemic BMSCs treated with both ATRA and amphotericin-B. Data are presented as mean ± SD.Single asterisk indicates significant difference (P < 0.05)
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