Membrane transporters and channels (collectively the transportome) govern cellular influx and efflux of
ions, nutrients, and drugs. We used
oligonucleotide arrays to analyze gene expression of the transportome in 60 human
cancer cell lines used by the National Cancer Institute for
drug screening. Correlating gene expression with the potencies of 119 standard anticancer drugs identified known
drug-transporter interactions and suggested novel ones.
Folate,
nucleoside, and
amino acid transporters positively correlated with chemosensitivity to their respective
drug substrates. We validated the positive correlation between SLC29A1 (
nucleoside transporter ENT1) expression and potency of
nucleoside analogues,
azacytidine and
inosine-glycodialdehyde. Application of an inhibitor of SLC29A1, nitrobenzylmercaptopurine ribonucleoside, significantly reduced the potency of these two drugs, indicating that SLC29A1 plays a role in cellular uptake. Three ABC efflux transporters (ABCB1, ABCC3, and ABCB5) showed significant negative correlations with multiple drugs, suggesting a mechanism of drug resistance. ABCB1 expression correlated negatively with potencies of 19 known ABCB1 substrates and with
Baker's antifol and
geldanamycin. Use of RNA interference reduced ABCB1
mRNA levels and concomitantly increased sensitivity to these two drugs, as expected for ABCB1 substrates. Similarly, specific silencing of ABCB5 by
small interfering RNA increased sensitivity to several drugs in
melanoma cells, implicating ABCB5 as a novel chemoresistance factor. Ion exchangers,
ion channels, and subunits of
proton and
sodium pumps variably correlated with
drug potency. This study identifies numerous potential
drug-transporter relationships and supports a prominent role for membrane transport in determining chemosensitivity. Measurement of transporter gene expression may prove useful in predicting anticancer
drug response.