Membrane transporters and channels: role of the transportome in cancer chemosensitivity and chemoresistance.
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.
Huang
Ying
Y
Program of Pharmacogenomics, Department of Pharmacology, College of Medicine and Public Health, The Ohio State University, Columbus, 43210, USA.
Anderle
Pascale
P
Bussey
Kimberly J
KJ
Barbacioru
Catalin
C
Shankavaram
Uma
U
Dai
Zunyan
Z
Reinhold
William C
WC
Papp
Audrey
A
Weinstein
John N
JN
Sadée
Wolfgang
W
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference
D018528:ATP-Binding Cassette Transporters; D026905:Amino Acid Transport Systems; D000970:Antineoplastic Agents; D007473:Ion Channels; D009363:Neoplasm Proteins; D000251:Adenosine Triphosphatases