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The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells

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Abstract

For decades, cancer was associated with gap-junction defects. However, more recently it appeared that the gap junction proteins (connexins) could be re-expressed and participate to cancer cell dissemination during the late stages of tumor progression. Since primary tumors of prostate cancer (PCa) are known to be connexin deficient, it was interesting to verify whether their bone-targeted metastatic behaviour could be influenced by the re-expression of the connexin type (connexin43) which is originally present in prostate tissue and highly expressed in bone where it participates to the differentiation of osteoblastic cells. Thus, we investigated the effect of the increased Cx43 expression, by retroviral infection, on the metastatic behaviour of two well-characterized cell lines (PC-3 and LNCaP) representing different stages of PCa progression. It appeared that Cx43 differently behaved in those cell lines and induced different phenotypes. In LNCaP, Cx43 was functional, localized at the plasma membrane and its high expression was correlated with a more aggressive phenotype both in vitro and in vivo. In particular, those Cx43-expressing LNCaP cells exhibited a high incidence of osteolytic metastases generated by bone xenografts in mice. Interestingly, LNCaP cells were also able to decrease the proliferation of cocultured osteoblastic cells. In contrast, the increased expression of Cx43 in PC-3 cells led to an unfunctional, cytoplasmic localization of the protein and was correlated with a reduction of proliferation, adhesion and invasion of the cells. In conclusion, the localization and the functionality of Cx43 may govern the ability of PCa cells to metastasize in bones.

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Abbreviations

μCT:

Micro-Computed Tomography

ALP:

Alkaline phosphatase

BMP3:

Bone morphogenic protein-3

Cx43:

Connexin43

DAG1:

Dystroglycan-1

Gap-FRAP:

Gap-fluorescence recovery after photobleaching

GJIC:

Gap junctional intercellular communication

LGALS1:

Galectin-1

MDP:

Methylene diphosphonate

MMP13:

Matrix metalloproteinase-13

NOV/CCN3:

Nephroblastoma overexpressed gene/connective tissue growth factor3

OB:

Osteoblastic

OCN:

Osteocalcin

OPG:

Osteoprotegerin

OPN:

Osteopontin

PCa:

Prostate cancer

PLAT:

Plasminogen activator tissue-type

PTX-3:

Pentraxin-related protein-3

RANKL:

Receptor activator of nuclear factor-kappaB ligand

TIMP2:

MetalloProteinase inhibitor-2

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Acknowledgments

This work was supported by the French Society of Rheumatology (SFR); the “Ligue Nationale contre le Cancer” and The Canadian Institutes of Health Research (CCN, LJF). C. Lamiche is supported by grants from the region “Poitou–Charentes”. We are most grateful to Drs A. Le Pape and S. Lerondel (CIPA, CNRS, TAAM UPS 44, Orléans, France) for their expert assistance during in vivo experiments. The authors would like to thank Dr A.C. Balandre, N. Stoynov and L. Le Scouarnec for their technical support.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. CNRS, UMR6187, Institute of Cellular Physiology and Biology, University of Poitiers, Bat. B36, 1, rue G. Bonnet, BP 633, 86022, Poitiers Cedex, France

    Coralie Lamiche, Jonathan Clarhaut, Pierre-Olivier Strale, Sophie Crespin, Norah Defamie, Marc Mesnil, Françoise Debiais & Laurent Cronier

  2. INSERM CIC 0802, C.H.U. la Milétrie, Poitiers, France

    Jonathan Clarhaut

  3. BIOAlternatives, Gençay, France

    Nathalie Pedretti & François-Xavier Bernard

  4. Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada

    Christian C. Naus & Vincent C. Chen

  5. Centre for High-Throughput Biology, University of British Columbia, Vancouver, BC, Canada

    Vincent C. Chen & Leonard J. Foster

  6. Department of Rheumatology, C.H.U. la Milétrie, Poitiers, France

    Françoise Debiais

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  1. Coralie Lamiche
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  2. Jonathan Clarhaut
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  11. Marc Mesnil
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  12. Françoise Debiais
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  13. Laurent Cronier
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Correspondence to Laurent Cronier.

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Lamiche, C., Clarhaut, J., Strale, PO. et al. The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells. Clin Exp Metastasis 29, 111–122 (2012). https://doi.org/10.1007/s10585-011-9434-4

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