Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins.
As cellular folate levels seem to have a different effect on cancer cells from different origins, we extended our initial study to a broader panel of cancer cells. BCRP and MRP1-5 expression was determined in KB, OVCAR-3, IGROV-1, ZR75-1/R/MTX, SCC-11B, SCC-22B, and WiDr either grown in standard RPMI 1640 containing 2.3 micromol/L supraphysiologic concentration of folic acid [high folate (HF)] or adapted to more physiologic concentrations [1-5 nmol/L folic acid or leucovorin; low folate (LF)]. Compared with the HF counterparts, KB LF cells displayed 16.1-fold increased MRP3 and OVCAR-3 LF cells showed 4.8-fold increased MRP4 mRNA levels along with increased MRP3 and MRP4 protein expression, respectively. A marked increase on BCRP protein and mRNA expression was observed in WiDr LF cells. These cells acquired approximately 2-fold resistance to mitoxantrone compared with the HF cell line, a phenotype that could be reverted by the BCRP inhibitor Ko143. Of note, WiDr cells expressed BCRP in the intracellular compartment, similarly to what we have described for Caco-2 cells. Our results provide further evidence for an important role of cellular folate status in the modulation of the expression of multidrug resistance transporters in cancer cells. We show that up-regulation of intracellularly localized BCRP in response to adaptation to LF conditions may be a common feature within a panel of colon cancer cell lines. Under these circumstances, folate supplementation might improve the efficacy of chemotherapeutic drugs by decreasing BCRP expression.
Lemos
Clara
C
Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal. lemosc@gmail.com
Kathmann
Ietje
I
Giovannetti
Elisa
E
Beliën
Jeroen A M
JA
Scheffer
George L
GL
Calhau
Conceição
C
Jansen
Gerrit
G
Peters
Godefridus J
GJ
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000222:Adaptation, Physiological / Q000187:drug effects / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019450:Genes, MDR; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D005492:Folic Acid; D026901:Membrane Transport Proteins; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010453:Peptide Synthases; D013762:Tetrahydrofolate Dehydrogenase; C116614:ABCG2 protein, human; C120043:SLC19A2 protein, human; C023103:folylpolyglutamate synthetase; C421109:multidrug resistance-associated protein 1