Abstract
Simple SummaryCanine mammary tumor is one of the most prevalent canine tumor types in China. Clinical studies showed that the high expression of mucin 1 (MUC1) protein is significantly associated with the malignancy and poor prognosis of canine mammary tumor. Therefore, it is worthwhile to investigate the expression of mucin 1 in developing treatments against canine mammary tumors. In the present study, it is demonstrated that disulfiram, an approved medication in treating human alcoholism, also has inhibitory effects on the growth of canine mammary tumor cells both in vitro and in vivo. With the overexpression of MUC1, the inhibitory effects of disulfiram decrease accordingly. Moreover, disulfiram is shown to inhibit phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (Akt) signaling transduction, which is attenuated by MUC1 overexpression. Overall, these results indicate that the expression level of MUC1 is detrimental to determining the anti-tumor activity of disulfiram. Further consideration should be given when treating the canine mammary tumor with disulfiram or other PI3K/Akt inhibitors.Mucin 1 (MUC1), a transmembrane protein, is closely associated with the malignancy and metastasis of canine mammary tumors; however, the role of overexpressed MUC1 in the development of cancer cells and response to drug treatment remains unclear. To address this question, we developed a new canine mammary tumor cell line, CIPp-MUC1, with an elevated expression level of MUC1. In vitro studies showed that CIPp-MUC1 cells are superior in proliferation and migration than wild-type control, which was associated with the upregulation of PI3K, p-Akt, mTOR, Bcl-2. In addition, overexpression of MUC1 in CIPp-MUC1 cells inhibited the suppressing activity of disulfiram on the growth and metastasis of tumor cells, as well as inhibiting the pro-apoptotic effect of disulfiram. In vivo studies, on the other side, showed more rapid tumor growth and stronger resistance to disulfiram treatment in CIPp-MUC1 xenograft mice than in wild-type control. In conclusion, our study demonstrated the importance of MUC1 in affecting the therapeutical efficiency of disulfiram against canine mammary tumors, indicating that the expression level of MUC1 should be considered for clinical use of disulfiram or other drugs targeting PI3K/Akt pathway.
Highlights
In the present study, it is demonstrated that disulfiram, an approved medication in treating human alcoholism, has inhibitory effects on the growth of canine mammary tumor cells both in vitro and in vivo
phosphoinositide 3-kinase (PI3K), p-Akt, and mTOR was higher in CIPp-Mucin 1 (MUC1) cells (Figure S1b)
These results suggested that overexpression of MUC1 leads to the upregulation of PI3K/Akt signaling pathway
Summary
It is demonstrated that disulfiram, an approved medication in treating human alcoholism, has inhibitory effects on the growth of canine mammary tumor cells both in vitro and in vivo. Disulfiram is shown to inhibit phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (Akt) signaling transduction, which is attenuated by MUC1 overexpression Overall, these results indicate that the expression level of MUC1 is detrimental to determining the anti-tumor activity of disulfiram. Mucin 1 (MUC1), a transmembrane protein, is closely associated with the malignancy and metastasis of canine mammary tumors; the role of overexpressed MUC1 in the development of cancer cells and response to drug treatment remains unclear. To address this question, we developed a new canine mammary tumor cell line, CIPp-MUC1, with an elevated expression level of MUC1. Previous studies focusing on metastatic canine mammary tumors have found that MUC1 is overexpressed in both primary and metastatic sites, as well as in metastatic lymph nodes, with a statistically significant correlation between the expression level of MUC1 and distant metastasis of tumor [13,14]
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