Hanne Verswyvel

Chapter 5 │ Page 176 Cx43 overexpression could attenuate EMT and improve the sensitivity of cancer cells to the chemotherapeutic drug tamoxifen [120]. EMT is an important event to confer tamoxifen resistance, and overexpression of Cx43 proteins was su icient to inhibit TGF-β1-induced EMT activation, and to retard PI3K/Akt activation, a signaling pathway that plays a vital role in initiating EMT and drug resistance in di erent malignancies [120]. Altogether, these results show that enhancing the tumor-suppressive functions of Cx43 proteins and GJs has the potential to be combined with chemotherapeutic agents in order to overcome chemoresistance. Due to the paradoxical anti- and pro-tumorigenic role of Cxs and GJs in cancer cells, therapeutic strategies to inhibit Cxs and GJs when they may act as tumor promoter have also emerged [20,21]. Considering that the CT domain of Cxs plays a pivotal role in the regulation of GJ function [22,121,122], manipulation of its secondary structure can help in the regulation of GJ function. For instance, peptides that mimic the CT domain of Cxs have been used to block GJs function [22,23,28]. An example of a clinically tested therapeutic peptide is the alpha connexin carboxyterminus 1 (αCT1), a selective inhibitor of Cx43-GJs that mimics the CT domain of Cx43 proteins. Administration of αCT1 restored the sensitivity of resistant glioblastoma cells to temozolomide chemotherapy [28]. The combination of αCT1 and temozolomide induced autophagy and apoptosis in those tumor cells, through attenuation of AkT/MTOR activity, signaling pathway known to induce temozolomide-resistance [28]. Due to the tumor-sensitizing capacities, multiple cell-penetrating mimetic peptides targeting di erent Cx domains and Cx types are currently developed in an attempt to improve remaining shortcomings, like target specificity and selectivity [123]. Once these problems are overcome, Cx manipulation - and in specific Cx43 proteins - via mimetic peptides is a very promising combination strategy for tumoral management with clinical applications.

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