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Connexin membrane materials as potent inhibitors of breast cancer cell migration.

ABSTRACT: Gap junction (GJ) channels facilitate cell-cell communication through the exchange of chemical and mechanical signals, ensuring proper tissue development and homeostasis. The complex, disease stage-dependent role of connexins in breast cancer progression has been extensively studied over the past two decades. In the early stages of breast cancer, substantial evidence supports the role of GJ channels, formed by connexins at the interfaces between neighbouring cells, as suppressors of cell migration and proliferation. These findings suggest that materials that reintroduce connexins into the tumour cell environment have the potential to inhibit cell migration. Here, we report that exposure of highly metastatic MDA-MB-231 breast tumour cells to connexin-rich biovesicle materials potently suppresses cell migration. Specifically, these biovesicles, which can form GJ interfaces with cells, were extracted from the plasma membrane of donor cells engineered to express a high concentration of functional connexin 43 channels. These connexin-rich membrane materials dramatically reduced cell migration in both a transwell migration assay and a scratch closure assay. Collectively, these results suggest that using membrane materials to reintroduce connexins into the tumour cell environment provides a novel approach for combating cell migration and invasion.

SUBMITTER: Ferrati S

PROVIDER: S-EPMC5582126 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Connexin membrane materials as potent inhibitors of breast cancer cell migration.

Ferrati Silvia S Gadok Avinash K AK Brunaugh Ashlee D AD Zhao Chi C Heersema Lara A LA Smyth Hugh D C HDC Stachowiak Jeanne C JC

Journal of the Royal Society, Interface 20170801 133

Gap junction (GJ) channels facilitate cell-cell communication through the exchange of chemical and mechanical signals, ensuring proper tissue development and homeostasis. The complex, disease stage-dependent role of connexins in breast cancer progression has been extensively studied over the past two decades. In the early stages of breast cancer, substantial evidence supports the role of GJ channels, formed by connexins at the interfaces between neighbouring cells, as suppressors of cell migrati ...[more]

PMID: 28768882

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Project description:Despite their lack of selectivity toward c-Jun N-terminal kinase (JNK) isoforms, peptides derived from the JIP (JNK Interacting Protein) scaffolds linked to the cell-penetrating peptide TAT are widely used to investigate JNK-mediated signaling events. To engineer an isoform-selective peptide inhibitor, several JIP-based peptide sequences were designed and tested. A JIP sequence connected through a flexible linker to either the N-terminus of an inverted TAT sequence (JIP(10)-?-TAT(i)) or to a poly arginine sequence (JIP(10)-?-R(9)) enabled the potent inhibition of JNK2 (IC(50) ? 90 nM) and exhibited 10-fold selectivity for JNK2 over JNK1 and JNK3. Examination of both peptides in HEK293 cells revealed a potent ability to inhibit the induction of both JNK activation and c-Jun phosphorylation in cells treated with anisomycin. Notably, Western blot analysis indicates that only a fraction of total JNK must be activated to elicit robust c-Jun phosphorylation. To examine the potential of each peptide to selectively modulate JNK2 signaling in vivo, their ability to inhibit the migration of Polyoma Middle-T Antigen Mammary Tumor (PyVMT) cells was assessed. PyVMTjnk2-/- cells exhibit a lower migration potential compared to PyVMTjnk2+/+ cells, and this migration potential is restored through the overexpression of GFP-JNK2?. Both JIP(10)-?-TAT(i) and JIP(10)-?-R(9) inhibit the migration of PyVMTjnk2+/+ cells and PyVMTjnk2-/- cells expressing GFP-JNK2?. However, neither peptide inhibits the migration of PyVMTjnk2-/- cells. A control form of JIP(10)-?-TAT(i) containing a single leucine to arginine mutation lacks ability to inhibit JNK2 in vitro cell-free and cell-based assays and does not inhibit the migration of PyVMTjnk2+/+ cells. Together, these data suggest that JIP(10)-?-TAT(i) and JIP(10)-?-R(9) inhibit the migration of PyVMT cells through the selective inhibition of JNK2. Finally, the mechanism of inhibition of a D-retro-inverso JIP peptide, previously reported to inhibit JNK, was examined and found to inhibit p38MAPK? in an in vitro cell-free assay with little propensity to inhibit JNK isoforms.

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Connexin membrane materials as potent inhibitors of breast cancer cell migration.

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Connexin membrane materials as potent inhibitors of breast cancer cell migration.

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