Abstract
Oral mucosal melanomas (OMM) are aggressive cancers in dogs, and are good models for human OMM. Gap junctions are composed of connexin units, which may have altered expression patterns and/or subcellular localization in cancer cells. Cell-to-cell communication by gap junctions is often impaired in cancer cells, including in melanomas. Meanwhile, the upregulated expression of the gap junction protein connexin 43 (Cx43) inhibits melanoma progression. The α-connexin carboxyl-terminal (aCT1) peptide reportedly maintains Cx43 expression and cell-cell communication in human mammary cells and increases the communication activity through gap junctions in functional assays, therefore causing decreased cell proliferation. The Bowman-Birk protease inhibitor (BBI), a component of soybeans, induces Cx43 expression in several tumor cells as a trypsin–chymotrypsin inhibition function, with antineoplastic effects. This study investigated the effect of aCT1 peptide and BBI treatment, alone or in combination, on TLM1 canine melanoma cell viability. Cell viability after treatment with aCT1, the reverse sequence peptide (R-pep), and/or BBI for 5 days was analyzed by PrestoBlue assay. Immunofluorescence was used to observe Cx43 localization and expression. aCT1 (200 μM) alone did not significantly decrease cell viability in TLM1 cells, whereas BBI (400 μg/ml) alone significantly decreased the TLM1 viability. Combined treatment with both aCT1 (200 μM) and BBI (400 μg/ml) significantly decreased cell viability in TLM1 cells. Cx43 expression, as identified by immunostainings in TLM1 cells, was increased in the cell membrane after the combination treatment with BBI and aCT1. This dual treatment can be combined to achieve the anticancer activity, possibly by increasing Cx 43 expression and affecting Cx43 migration to the cell membrane. In conclusion, a treatment strategy targeting Cx43 with BBI and aCT1 may possibly lead to new effective therapies for canine OMM.
Highlights
Melanoma is an aggressive skin and mucosal cancer that develops from melanocytes
The aCT1 peptide is a short sequence at the connexin 43 (Cx43) C-terminus, and this is linked to an antennapedia internalization sequence (RQPKIWFPNRRKPWKKRPRPDDLEI)
Cell viability assays were carried out to evaluate the effects of aCT1 peptide in canine Oral mucosal melanomas (OMM) TLM1 cells by treating them with 200 μM aCT1 peptide or reverse sequence peptide (R-pep). aCT1 peptide alone showed no effect on cell viability in the TLM1 cells
Summary
Melanoma is an aggressive skin and mucosal cancer that develops from melanocytes. This tumor arises due to random genetic mutations, and after the melanoma has spread, it rapidly becomes life-threatening [1]. The diagnosis of early-stage melanomas can facilitate their cure by surgical resection, and approximately 80% of cases are treated in this manner. Metastatic melanoma is largely refractory to the existing therapies and has a very poor prognosis, being the survival rate for 5years lower than 15% of the cases [2]. Continued research into more effective therapies for melanoma will improve the treatment and prognosis of these patients
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