Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells

Due to the size, glycosylation, and location in the plasma membrane of the sialomucin complex Muc4, which has been implicated in ErbB2 signaling, in the repression of apoptosis and cell adhesion, and in tumor metastasis, studies were initiated to determine whether its presence could influence cell sensitivity to anticancer drugs. Growth inhibition assays using melanoma cell lines that either express the glycoprotein (Muc4⁺) or do not (Muc4^-) showed that Muc4 renders cells resistant to taxol, doxorubicin, vinblastine, rhodamine 123, and 2-deoxyglucose. When treated with various concentrations of doxorubicin, Muc4⁺ cells were blocked less frequently in G₂ and underwent less DNA fragmentation (apoptosis and/or necrosis) than Muc4^- cells. All of the drugs tested (except for 2-deoxyglucose) are well recognized by P-glycoprotein-mediated multidrug resistance 1 (MDR1) and to a lesser degree by multidrug resistance related protein 1 (MRP1) transporters. Therefore, transporter gene expression in these cells was assayed. Surprisingly, Muc4⁺ cells expressed lower levels of both transporter genes than Muc4^- cells. Moreover, rhodamine 123 was retained more highly in the Muc4⁺ than in the Muc4^- cells, demonstrating that these transporters are functional. Overall, these results indicate that although Muc4⁺ cells express less MDR1 and MRP1, they are more resistant to drugs recognized by these transporters.