TY - JOUR
T1 - Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells
AU - Hu, Yan Ping
AU - Haq, Bushra
AU - Carraway, Kermit L.
AU - Savaraj, Niramol
AU - Lampidis, Theodore J.
N1 - Funding Information:
FACScan analyses were done at the Flow Cytometry Facility of the Sylvester Cancer Center of the University of Miami under the expert supervision of James Phillips. This work was supported by NCI Grants CA37109 to T.J.L. and CA52498 and CA74072 to K.L.C.
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
KW - Melanoma
KW - MRP
KW - Muc4
KW - Multidrug resistance
KW - P-gp
KW - Rhodamine 123
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U2 - 10.1016/S0006-2952(03)00086-8
DO - 10.1016/S0006-2952(03)00086-8
M3 - Article
C2 - 12732353
AN - SCOPUS:0038403798
VL - 65
SP - 1419
EP - 1425
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 9
ER -