Targeting connexin 43 with α–connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1

Abstract

BackgroundTreatment failure is a critical issue in breast cancer and identifying useful interventions that optimize current cancer therapies remains a critical unmet need. Expression and functional studies have identified connexins (Cxs), a family of gap junction proteins, as potential tumor suppressors. Studies suggest that Cx43 has a role in breast cancer cell proliferation, differentiation, and migration. Although pan-gap junction drugs are available, the lack of specificity of these agents increases the opportunity for off target effects. Consequently, a therapeutic agent that specifically modulates Cx43 would be beneficial and has not been tested in breast cancer. In this study, we now test an agent that specifically targets Cx43, called ACT1, in breast cancer.MethodsWe evaluated whether direct modulation of Cx43 using a Cx43-directed therapeutic peptide, called ACT1, enhances Cx43 gap junctional activity in breast cancer cells, impairs breast cancer cell proliferation or survival, and enhances the activity of the targeted inhibitors tamoxifen and lapatinib.ResultsOur results show that therapeutic modulation of Cx43 by ACT1 maintains Cx43 at gap junction sites between cell-cell membrane borders of breast cancer cells and augments gap junction activity in functional assays. The increase in Cx43 gap junctional activity achieved by ACT1 treatment impairs proliferation or survival of breast cancer cells but ACT1 has no effect on non-transformed MCF10A cells. Furthermore, treating ER+ breast cancer cells with a combination of ACT1 and tamoxifen or HER2+ breast cancer cells with ACT1 and lapatinib augments the activity of these targeted inhibitors.ConclusionsBased on our findings, we conclude that modulation of Cx43 activity in breast cancer can be effectively achieved with the agent ACT1 to sustain Cx43-mediated gap junctional activity resulting in impaired malignant progression and enhanced activity of lapatinib and tamoxifen, implicating ACT1 as part of a combination regimen in breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1229-6) contains supplementary material, which is available to authorized users.

Gap junctions and cancer: communicating for 50 years

“…For instance, a peptide (αCT1) mimicking the C-terminal of Cx43, blocking ZO1 interacting with Cx43, was shown to cause specific inhibition of Cx43 hemichannel function (but maintaining GJIC), which prevented temozolomide resistance in human glioblastoma cell lines 237 . In another study the same peptide augmented the effect of the oestrogen receptor modulator tamoxifen and the ERBB2 inhibitor lapatinib in breast cancer cell lines, although the authors suggested the key function of the peptide in this setting was to enhance GJIC 238 . The exact mode of action of this peptide appears complex and perhaps even context-dependent.…”

Connexin channel and its role in diabetic retinopathy

“…Later, more specific approaches have been developed including siRNA and short peptides with specific sequences homologous to intracellular and extracellular connexin domains, termed connexin mimetic peptides (Iyyathurai et al, 2013). ACT1 peptide targeting a portion of Cx43 C-terminus enhances GJIC for potential therapies in wound healing and cancer (Grek et al, 2015a; Grek et al, 2015b). Given that connexin hemichannels operate independently of gap junctions and also serve different roles in cell physiology and pathology, several peptides that target to extracellular loop regions of Cx43 have been developed and some of them exhibit stronger inhibitory effects against hemichannels than GJIC.…”

Identification of miR-200a as a novel suppressor of connexin 43 in breast cancer cells

“…Cx43 expression was associated with increased malignancy in multiple cancers [26][27][28]. Especially, a previous study reported that miR-206 inhibited the migration and invasion of breast cancer by targeting at Cx43 [25].…”