This Article Full Text Full Text (PDF) Supplementary Data Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huang, Y. Articles by Sadée, W. Search for Related Content PubMed PubMed Citation Articles by Huang, Y. Articles by Sadée, W.

Membrane Transporters and Channels

Role of the Transportome in Cancer Chemosensitivity and Chemoresistance

¹ Program of Pharmacogenomics, Department of Pharmacology, ² Department of Biomedical Informatics, College of Medicine and Public Health, and the ¹Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, and ³ Laboratory of Molecular Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland

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.

This article has been cited by other articles:

				S. Hu, Z. Chen, R. Franke, S. Orwick, M. Zhao, M. A. Rudek, A. Sparreboom, and S. D. Baker Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters Clin. Cancer Res., October 1, 2009; 15(19): 6062 - 6069. [Abstract] [Full Text] [PDF]

				J. N. Orina, A. M. Calcagno, C.-P. Wu, S. Varma, J. Shih, M. Lin, G. Eichler, J. N. Weinstein, Y. Pommier, S. V. Ambudkar, et al. Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database Mol. Cancer Ther., July 1, 2009; 8(7): 2057 - 2066. [Abstract] [Full Text] [PDF]

				J. L. Vega, C. Puebla, R. Vasquez, M. Farias, J. Alarcon, M. Pastor-Anglada, B. Krause, P. Casanello, and L. Sobrevia TGF-{beta}1 inhibits expression and activity of hENT1 in a nitric oxide-dependent manner in human umbilical vein endothelium Cardiovasc Res, June 1, 2009; 82(3): 458 - 467. [Abstract] [Full Text] [PDF]

				M. Rius, C. Stresemann, D. Keller, M. Brom, E. Schirrmacher, D. Keppler, and F. Lyko Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation Mol. Cancer Ther., January 1, 2009; 8(1): 225 - 231. [Abstract] [Full Text] [PDF]

				M. Okabe, G. Szakacs, M. A. Reimers, T. Suzuki, M. D. Hall, T. Abe, J. N. Weinstein, and M. M. Gottesman Profiling SLCO and SLC22 genes in the NCI-60 cancer cell lines to identify drug uptake transporters Mol. Cancer Ther., September 1, 2008; 7(9): 3081 - 3091. [Abstract] [Full Text] [PDF]

				S. A. Amundson, K. T. Do, L. C. Vinikoor, R. A. Lee, C. A. Koch-Paiz, J. Ahn, M. Reimers, Y. Chen, D. A. Scudiero, J. N. Weinstein, et al. Integrating Global Gene Expression and Radiation Survival Parameters across the 60 Cell Lines of the National Cancer Institute Anticancer Drug Screen Cancer Res., January 15, 2008; 68(2): 415 - 424. [Abstract] [Full Text] [PDF]

				P. E. Blower, J.-H. Chung, J. S. Verducci, S. Lin, J.-K. Park, Z. Dai, C.-G. Liu, T. D. Schmittgen, W. C. Reinhold, C. M. Croce, et al. MicroRNAs modulate the chemosensitivity of tumor cells Mol. Cancer Ther., January 1, 2008; 7(1): 1 - 9. [Abstract] [Full Text] [PDF]

				R. Liu, P. E. Blower, A.-N. Pham, J. Fang, Z. Dai, C. Wise, B. Green, C. H. Teitel, B. Ning, W. Ling, et al. Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin Mol. Pharmacol., December 1, 2007; 72(6): 1637 - 1646. [Abstract] [Full Text] [PDF]

				P. E. Blower, J. S. Verducci, S. Lin, J. Zhou, J.-H. Chung, Z. Dai, C.-G. Liu, W. Reinhold, P. L. Lorenzi, E. P. Kaldjian, et al. MicroRNA expression profiles for the NCI-60 cancer cell panel Mol. Cancer Ther., May 1, 2007; 6(5): 1483 - 1491. [Abstract] [Full Text] [PDF]

				M. I. Al-Salabi, L. J. M. Wallace, A. Luscher, P. Maser, D. Candlish, B. Rodenko, M. K. Gould, I. Jabeen, S. N. Ajith, and H. P. de Koning Molecular Interactions Underlying the Unusually High Adenosine Affinity of a Novel Trypanosoma brucei Nucleoside Transporter Mol. Pharmacol., March 1, 2007; 71(3): 921 - 929. [Abstract] [Full Text] [PDF]

				U. T. Shankavaram, W. C. Reinhold, S. Nishizuka, S. Major, D. Morita, K. K. Chary, M. A. Reimers, U. Scherf, A. Kahn, D. Dolginow, et al. Transcript and protein expression profiles of the NCI-60 cancer cell panel: an integromic microarray study Mol. Cancer Ther., March 1, 2007; 6(3): 820 - 832. [Abstract] [Full Text] [PDF]

				W. C. Reinhold, M. A. Reimers, A. K. Maunakea, S. Kim, S. Lababidi, U. Scherf, U. T. Shankavaram, M. S. Ziegler, C. Stewart, H. Kouros-Mehr, et al. Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells Mol. Cancer Ther., February 1, 2007; 6(2): 391 - 403. [Abstract] [Full Text] [PDF]

				S. Zhang, K. S. Lovejoy, J. E. Shima, L. L. Lagpacan, Y. Shu, A. Lapuk, Y. Chen, T. Komori, J. W. Gray, X. Chen, et al. Organic Cation Transporters Are Determinants of Oxaliplatin Cytotoxicity. Cancer Res., September 1, 2006; 66(17): 8847 - 8857. [Abstract] [Full Text] [PDF]

				H. Hu, C. J. Endres, C. Chang, N. S. Umapathy, E.-W. Lee, Y.-J. Fei, S. Itagaki, P. W. Swaan, V. Ganapathy, and J. D. Unadkat Electrophysiological Characterization and Modeling of the Structure Activity Relationship of the Human Concentrative Nucleoside Transporter 3 (hCNT3) Mol. Pharmacol., May 1, 2006; 69(5): 1542 - 1553. [Abstract] [Full Text] [PDF]

				W. Sadee and Z. Dai Pharmacogenetics/genomics and personalized medicine Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214. [Abstract] [Full Text] [PDF]

				V. Prasad, G. P. Boivin, M. L. Miller, L. H. Liu, C. R. Erwin, B. W. Warner, and G. E. Shull Haploinsufficiency of Atp2a2, Encoding the Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2 Ca2+ Pump, Predisposes Mice to Squamous Cell Tumors via a Novel Mode of Cancer Susceptibility Cancer Res., October 1, 2005; 65(19): 8655 - 8661. [Abstract] [Full Text] [PDF]

				G. Zaza, M. Cheok, W. Yang, J. C. Panetta, C.-H. Pui, M. V. Relling, and W. E. Evans Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment Blood, September 1, 2005; 106(5): 1778 - 1785. [Abstract] [Full Text] [PDF]

				Y. Huang, Z. Dai, C. Barbacioru, and W. Sadee Cystine-Glutamate Transporter SLC7A11 in Cancer Chemosensitivity and Chemoresistance Cancer Res., August 15, 2005; 65(16): 7446 - 7454. [Abstract] [Full Text] [PDF]

				J. J. Xiao, Y. Huang, Z. Dai, W. Sadee, J. Chen, S. Liu, G. Marcucci, J. Byrd, J. M. Covey, J. Wright, et al. Chemoresistance to Depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-Ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] Is Mediated by Reversible MDR1 Induction in Human Cancer Cell Lines J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 467 - 475. [Abstract] [Full Text] [PDF]

				N. Y. Frank, A. Margaryan, Y. Huang, T. Schatton, A. M. Waaga-Gasser, M. Gasser, M. H. Sayegh, W. Sadee, and M. H. Frank ABCB5-Mediated Doxorubicin Transport and Chemoresistance in Human Malignant Melanoma Cancer Res., May 15, 2005; 65(10): 4320 - 4333. [Abstract] [Full Text] [PDF]

				J. J. Xiao, A. B. Foraker, P. W. Swaan, S. Liu, Y. Huang, Z. Dai, J. Chen, W. Sadee, J. Byrd, G. Marcucci, et al. Efflux of Depsipeptide FK228 (FR901228, NSC-630176) Is Mediated by P-Glycoprotein and Multidrug Resistance-Associated Protein 1 J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 268 - 276. [Abstract] [Full Text] [PDF]