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

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.

Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication

“…In particular, Cx43-mediated heterocellular GJIC between cancer cells and their surrounding cells have been reported to promote metastasis in human gastric cancer [21], prostate cancer [22], and glioma [23]. In the present study, we demonstrated that GJIC was formed not only among CAFs or NSCLC cells themselves (homocellular GJIC) but also from CAFs to NSCLC cells (heterocellular GJIC), while the lack of GJIC from NSCLC cells to CAFs suggests that asymmetric unidirectional GJIC is present from CAFs to NSCLC cells.…”

“…Although connexins and their derived GJIC have long been considered tumor suppressors over the past 50 years [15,16,17], growing evidence suggests that they also contribute to malignant progression during the late stages of some cancer types [13,15,18]. In particular, heterocellular GJIC between cancer cells and adjacent cells, such as endothelial cells, mesothelial cells, osteoblastic cells, and astrocytes, has been demonstrated to play a crucial role in facilitating cancer invasion and metastasis [19,20,21,22,23,24]. Moreover, asymmetric heterologous GJIC has been observed from normal lung fibroblasts to human lung carcinoma cells [25].…”

Transforming growth factor-β stimulates human ovarian cancer cell migration by up-regulating connexin43 expression via Smad2/3 signaling

“…Indeed, overexpression experiments in two prostate cancer cell lines have demonstrated that overexpressed Cx43 is primarily localized in the cytoplasm of PC3 cells, whereas it is expressed in the plasma membrane of LNCaP cells. Interestingly, this differential localization of Cx43 leads to functional divergences as examined by cell proliferation, adhesion and invasion [36]. Generally, overexpression a specific protein may not always reflect its normal biological functions because the appropriate cellular localization of the overexpressed protein and the availability of its co-factors or downstream effectors are also important.…”

Suppression of CX43 expression by miR-20a in the progression of human prostate cancer

“…19,20 In breast cancer, the downregulation of CX43 significantly promotes tumor progression, 21 while the expression of CX43 could suppress the cancer phenotype of human mammary carcinoma cells and restore differentiation potential. 22 All the above these suggested that CX43 can function as a tumor suppressor.…”