Cellular folate status modulates the expression of BCRP and MRP multidrug transporters in cancer cell lines from different origins

• Published in: Molecular cancer therapeutics 2009-03, Vol.8 (3), p.655-664
• Main Authors: Lemos, Clara, Kathmann, Ietje, Giovannetti, Elisa, Beliën, Jeroen A M, Scheffer, George L, Calhau, Conceição, Jansen, Gerrit, Peters, Godefridus J
• Format: Article
• Language: English
• Subjects: Adaptation, Physiological - drug effects; Adaptation, Physiological - genetics; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; BCRP; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; folate status; Folic Acid - metabolism; Folic Acid - pharmacology; Folic Acid - physiology; Gene Expression Regulation, Neoplastic - drug effects; Genes, MDR; Humans; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mitoxantrone - pharmacology; MRP; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Peptide Synthases - genetics; Peptide Synthases - metabolism; Tetrahydrofolate Dehydrogenase - genetics; Tetrahydrofolate Dehydrogenase - metabolism; Tissue Distribution
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0768

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 μmol/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 ∼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. [Mol Cancer Ther 2009;8(3):655–64]