Up-regulation of CD147 and matrix metalloproteinase-2, -9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells.
Treatment of animals bearing multidrug resistant (MDR) tumor cells with P-glycoprotein (P-gp) substrates could worsen host survival. It is assumed that this is due to increased tumor metastasis. To clarify the mechanism(s) underlying this observation, the MDR human breast cancer cell line, MCF-7/AdrR, and its sensitive parental line, MCF-7, was treated with various concentrations of P-gp substrate drugs (vincristine, paclitoxel, adriamycin) and a P-gp non-substrate drug (bleomycin) in serum-free media. Increased production of CD147, and matrix metalloproteinases (MMP)-2, -9 was observed only in MDR cancer cells exposed to P-gp substrates, as determined using real-time polymerase chain reaction, western blotting and zymography. Correspondingly, P-gp substrates significantly enhanced the in vitro invasion abilities of MCF-7/Adr cells. It was also found that the drug-induced promotion of CD147, and MMP-2, -9 was consistent with increased expression of epidermal growth factor receptor (EGFR) and that inhibition of either EGFR or P-gp activity could significantly interrupt the downstream effects, and so inhibit in vitro invasion abilities motivated by P-gp substrates. These results imply that treatment of MDR tumors with P-gp substrates could adversely affect therapeutic outcomes through modulating the production of CD147, MMP-2, -9, and EGFR, and suggest that this effect may be initiated by the transporter function of P-gp.
Li
Qing-Quan
QQ
Department of Pathology, Shanghai Medical College, Fudan University, No. 138, Yixueyuan Road, Shanghai 200032, China.
Wang
Wen-Juan
WJ
Xu
Jing-Da
JD
Cao
Xi-Xi
XX
Chen
Qi
Q
Yang
Jin-Ming
JM
Xu
Zu-De
ZD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D051926:Basigin / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D000970:Antineoplastic Agents; D051926:Basigin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9