Increased expression of CX43 on stromal cells promotes leukemia apoptosis

Abstract

Connexin 43 (Cx43) induced apoptosis has been reported in solid tumors, but the effect of Cx43 expressed by bone marrow stromal cells (BMSC) in leukemia has not been fully investigated. Manipulating Cx43 expression could be a potential therapeutic strategy for leukemia. Here, we investigate the effect of Cx43 expressed by BMSCs (human Umbilical Cord Stem Cells over-expressed CX43, Cx43-hUCSC) on leukemia cells. When co-cultured with Cx43-hUCSC, leukemia cells show significant lower growth rate with increasing apoptosis activity, and more leukemia cells enter S phase. Functional assays of fluorescence recovery after photo bleaching (FRAP) showed improved gap junctional intercellular communication (GJIC) on leukemia cells when co-cultured with Cx43-hUCSC (p < 0.01). In a mouse minimal disease model, the mean survival time and mortality rate were significantly improved in mice transplanted with Cx43-hUCSC. Our results indicate that Cx43 expressed by BMSC induces apoptosis on leukemia cells. Small molecules or other pharmaceutical approaches for modulating Cx43 expression in BMSCs could be used for delaying relapse of leukemia.

Human-derived normal mesenchymal stem/stromal cells in anticancer therapies

“…UC-MSCs coculured with breast cancer cell line MDA-MB-231 can spontaneously generate hybrid/chimeric cell populations and induce expression of the GPI-anchored CD90 molecule in breast cancer cells, which can be partially blocked by a gap junction inhibitor in vitro and in vivo , leading to stimulation of breast cancer cell growth 70. Our previous study showed that increased expression of CX43 on UC-MSCs promotes leukemia apoptosis 71.…”

Gap Junctions in the Bone Marrow Lympho-Hematopoietic Stem Cell Niche, Leukemia Progression, and Chemoresistance

“…In contrast, others have reported that reduced Cx43 expression or deterioration of GJIC in BMSC is associated with leukemogenesis, while the upregulation of Cx43 GJIC in BMSC after chemotherapy or transfection with the Cx43 gene induces caspase 3 and 7 mediated apoptosis, and enhances the efficacy of therapies in hematologic malignancies [157][158][159][160][161]. In a minimal residual disease mouse model, the relapse of leukemia was delayed when mice were transplanted with human umbilical cord blood progenitors overexpressing Cx43 [160]. An antiproliferative effect of Cx43 was also observed in the U937 AML cell line expressing the AML1-ETO fusion protein, and it was mediated by the accumulation of p27 kip1 protein [162].…”

“…Of note, in vitro studies using OCI-AML3 and OCIM2 AML cell lines suggest that the higher expression of Cx43 in OCI-AML3 cells acts as a tumor promoter, which exerts its effect by promoting the exchange of growth factors; or by facilitating malignant cell proliferation and survival signal [156]. In contrast, others have reported that reduced Cx43 expression or deterioration of GJIC in BMSC is associated with leukemogenesis, while the upregulation of Cx43 GJIC in BMSC after chemotherapy or transfection with the Cx43 gene induces caspase 3 and 7 mediated apoptosis, and enhances the efficacy of therapies in hematologic malignancies [157][158][159][160][161]. In a minimal residual disease mouse model, the relapse of leukemia was delayed when mice were transplanted with human umbilical cord blood progenitors overexpressing Cx43 [160].…”

Regulation of tumor–stroma interactions by the unfolded protein response

“…In contrast, loss of direct cell–cell interaction and the lack of electrical coupling in cells are common features in many tumors. While tumor‐promoting chemicals and oncogenes inhibit GJIC, antitumor chemicals and anti‐oncogene drugs were associated with growth control and loss of tumorigenicity by re‐gaining GJIC activity . Moreover, the key proteins involved in GJIC, connexins are emerging as tumor suppressors .…”