Implications of ABCC4–Mediated cAMP Efflux for CRC Migration

SIMPLE SUMMARY: Cancer cells have developed a number of mechanisms to overcome anticancer therapy; the active efflux of drugs from cells via multidrug resistance proteins (MRPs) is one of them. MRPs belong to the superfamily of ATP binding cassette (ABC) proteins. It was hypothesized that the inhibition of ABC drug transporter activity during cancer therapy could sensitize drug-resistant tumors and/or improve the initial activity of anticancer agents. We demonstrated that the pharmacological inhibition of ABCC4 increases the migratory rate and invasive protrusion formation in colorectal cancer (CRC). Thus, during the use of ABCC4 inhibitors to reduce chemotherapy resistance or drugs that are potential substrates of ABCC4, the indirect effect on cancer metastasis should be taken into consideration and may be important in selecting a therapy scheme for patients. ABSTRACT: Colorectal cancer (CRC) presents significant molecular heterogeneity. The cellular plasticity of epithelial to mesenchymal transition (EMT) is one of the key factors responsible for the heterogeneous nature of metastatic CRC. EMT is an important regulator of ATP binding cassette (ABC) protein expression; these proteins are the active transporters of a broad range of endogenous compounds and anticancer drugs. In our previous studies, we performed a transcriptomic and functional analysis of CRC in the early stages of metastasis induced by the overexpression of Snail, the transcription factor involved in EMT initiation. Interestingly, we found a correlation between the Snail expression and ABCC4 (MRP4) protein upregulation. The relationship between epithelial transition and ABCC4 expression and function in CRC has not been previously defined. In the current study, we propose that the ABCC4 expression changes during EMT and may be differentially regulated in various subpopulations of CRC. We confirmed that ABCC4 upregulation is correlated with the phenotype conversion process in CRC. The analysis of Gene Expression Omnibus (GEO) sets showed that the ABCC4 expression was elevated in CRC patients. The results of a functional study demonstrated that, in CRC, ABCC4 can regulate cell migration in a cyclic nucleotide-dependent manner.