Gap junctional intercellular communication and connexin43 expression in human ovarian surface epithelial cells and ovarian carcinomas in vivo and in vitro

Abstract

Gap junctional intercellular communication (GJIC) and the expression of gap junction proteins (connexins) are frequently decreased in neoplastic cells and have been increased by cAMP and retinoids. GJIC and connexin expression were investigated in early passage normal human ovarian surface epithelial (HOSE) cells, human ovarian adenocarcinoma cell lines (CaOV-3, NIH:OVCAR-3, SK-OV-3 and SW626) and surgical specimens of human serous cystadenocarcinomas. We hypothesized that GJIC and connexin expression would be decreased in neoplastic cells and would be increased by cAMP and retinoic acid. Cultured HOSE cells exhibited extensive fluorescent dye-coupling and connexin43 (Cx43) expression; other connexins were not detected. The ovarian adenocarcinoma cell lines had little dye-coupling or connexin expression. Deletions and rearrangements of the Cx43 gene were not detected by Southern blotting in the carcinoma lines. N6, 2'-O-dibutyryladenosine 3',5'-cyclic monophosphate and all-trans-retinoic acid inhibited cell proliferation, but did not enhance GJIC or Cx43 expression. Surface epithelial cells of benign ovaries expressed Cx43, but this expression was barely detectable in ovarian serous cystadenocarcinomas. Thus, normal HOSE cells had extensive GJIC and Cx43 expression whereas ovarian carcinoma cells had less and cAMP and retinoic acid did not change these, although both agents inhibited cell growth.

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

“…In larger lung tumors, Cx32 and Cx40 are down-regulated, but Cx37, Cx43, and Cx45 are expressed (Isakson et al, 2001a(Isakson et al, ,b, 2003Udaka et al, 2006). In other cases, such as ovarian adenocarcinomas and cervical cancer, GJIC is dramatically reduced (Hanna et al, 1999;Umhauer et al, 2000;Aasen et al, 2005;Gershon et al, 2008). In this situation, because GJIC is already essentially absent, the effect of platinating reagents described in the present study would not occur, but in the former cases, the effect on the efficacy of the drugs due to effects on GJIC could occur.…”

Putting tumours in context

“…The particular composition of CONNEXIN subunits within a gap junction determines the type of molecule that can be transported 16 . Much remains to be learned about how the specific combination of connexins facilitates tissue interactions, but it is clear, again, that generalizations should be avoided, as the expression patterns (and probably the function) of connexins are tissue dependent and change during tumour progression 17,18 . For example, some breast cancer cells upregulate connexin 32 (Cx32) 19 , but loss of Cx32 contributes to hepatocellular carcinoma 20,21 ; Cx43 inhibits tumorigenicity of lung, cervical and bladder carcinoma cells [22][23][24] , but has no effect on squamous cell carcinomas 25 ; and other connexins can facilitate cell adhesion during metastasis 26 .…”

The phosphorylated form of connexin43 is up-regulated in breast hyperplasias and carcinomas and in their neoformed capillaries

“…With regard to transformation, a number of immunohistochemical and molecular studies have generally suggested an overall decrease in Cx43; this was the case in high-grade prostate carcinoma [10], in ovarian carcinomas in vivo and in vitro [11], in cervical dysplasia and the HeLa cell line [12], and in cutaneous basal and squamous cell carcinomas [13]. Data on Cxs in breast tumors are scanty; various reports pointed to a decreased Cx43 expression in some human and murine breast carcinomas and cell lines [14] and heterogeneous Cx43 reactivity in approximately 50% of breast carcinomas with staining of some stromal cells [15].…”