Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters.
Molecular and pharmacologic profiling of the NCI-60 cell panel offers the possibility of identifying pathways involved in drug resistance or sensitivity. Of these, decreased uptake of anticancer drugs mediated by efflux transporters represents one of the best studied mechanisms. Previous studies have also shown that uptake transporters can influence cytotoxicity by altering the cellular uptake of anticancer drugs. Using quantitative real-time PCR, we measured the mRNA expression of two solute carrier (SLC) families, the organic cation/zwitterion transporters (SLC22 family) and the organic anion transporters (SLCO family), totaling 23 genes in normal tissues and the NCI-60 cell panel. By correlating the mRNA expression pattern of the SLCO and SLC22 family member gene products with the growth-inhibitory profiles of 1,429 anticancer drugs and drug candidate compounds tested on the NCI-60 cell lines, we identified SLC proteins that are likely to play a dominant role in drug sensitivity. To substantiate some of the SLC-drug pairs for which the SLC member was predicted to be sensitizing, follow-up experiments were performed using engineered and characterized cell lines overexpressing SLC22A4 (OCTN1). As predicted by the statistical correlations, expression of SLC22A4 resulted in increased cellular uptake and heightened sensitivity to mitoxantrone and doxorubicin. Our results indicate that the gene expression database can be used to identify SLCO and SLC22 family members that confer sensitivity to cancer cells.
Okabe
Mitsunori
M
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Szakács
Gergely
G
Reimers
Mark A
MA
Suzuki
Toshihiro
T
Hall
Matthew D
MD
Abe
Takaaki
T
Weinstein
John N
JN
Gottesman
Michael M
MM
D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D008942:Mitoxantrone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D027981:Symporters; D014162:Transfection
D000970:Antineoplastic Agents; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C109807:SLC22A4 protein, human; D027981:Symporters; D004317:Doxorubicin; D008942:Mitoxantrone
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