All-trans-retinoic Acid Promotes Trafficking of Human Concentrative Nucleoside Transporter-3 (hCNT3) to the Plasma Membrane by a TGF-beta1-mediated Mechanism

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Feb 23

PMID 20172853

Citations 7

Authors

Paula Fernandez-Calotti

Marcal Pastor-Anglada

Affiliations

Soon will be listed here.

Abstract

Human concentrative nucleoside transporter-3 (hCNT3) is a sodium-coupled nucleoside transporter that exhibits high affinity and broad substrate selectivity, making it the most suitable candidate for mediating the uptake and cytotoxic action of most nucleoside-derived drugs. The drug of this class most commonly used in the treatment of chronic lymphocytic leukemia (CLL) is the pro-apoptotic nucleoside analog fludarabine (Flu), which enters CLL cells primarily through human equilibrative nucleoside transporters (hENTs). Although CLL cells lack hCNT3 activity, they do express this transporter protein, which is located mostly in the cytosol. The aim of our study was to identify agents and mechanisms capable of promoting hCNT3 trafficking to the plasma membrane. Here, we report that all-trans-retinoic acid (ATRA), currently used in the treatment of acute promyelocytic leukemia (APL), increases hCNT3-related activity through a mechanism that involves trafficking of pre-existing hCNT3 proteins to the plasma membrane. This effect is mediated by the autocrine action of transforming growth factor (TGF)-beta1, which is transcriptionally activated by ATRA in a p38-dependent manner. TGF-beta1 acts through activation of ERK1/2 and the small GTPase RhoA to promote plasma membrane trafficking of the hCNT3 protein.

Citing Articles

Nucleoside transporters and immunosuppressive adenosine signaling in the tumor microenvironment: Potential therapeutic opportunities.

Kaur T, Weadick B, Mace T, Desai K, Odom H, Govindarajan R Pharmacol Ther. 2022; 240:108300.

PMID: 36283452 PMC: 10290419. DOI: 10.1016/j.pharmthera.2022.108300.

The Antagonist of Retinoic Acid Receptor α, ER-50891 Antagonizes the Inhibitive Effect of All-Trans Retinoic Acid and Rescues Bone Morphogenetic Protein 2-Induced Osteoblastogenic Differentiation.

Wang S, Bi W, Liu Y, Cheng J, Sun W, Wu G Drug Des Devel Ther. 2020; 14:297-308.

PMID: 32158187 PMC: 6985983. DOI: 10.2147/DDDT.S215786.

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia.

Catala A, Pastor-Anglada M, Caviedes-Cardenas L, Malatesta R, Rives S, Vega-Garcia N Oncotarget. 2016; 7(31):49786-49799.

PMID: 27391351 PMC: 5226548. DOI: 10.18632/oncotarget.10448.

All-Trans Retinoic Acid Induces TGF-β2 in Intestinal Epithelial Cells via RhoA- and p38α MAPK-Mediated Activation of the Transcription Factor ATF2.

Namachivayam K, MohanKumar K, Arbach D, Jagadeeswaran R, Jain S, Natarajan V PLoS One. 2015; 10(7):e0134003.

PMID: 26225425 PMC: 4520553. DOI: 10.1371/journal.pone.0134003.

Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors.

Arimany-Nardi C, Errasti-Murugarren E, Minuesa G, Martinez-Picado J, Gorboulev V, Koepsell H Br J Pharmacol. 2014; 171(16):3868-80.

PMID: 24780098 PMC: 4128049. DOI: 10.1111/bph.12748.

References

Baldwin S, Beal P, Yao S, King A, Cass C, Young J . The equilibrative nucleoside transporter family, SLC29. Pflugers Arch. 2003; 447(5):735-43. DOI: 10.1007/s00424-003-1103-2. View

Gamberale R, Geffner J, Arrosagaray G, Scolnik M, Salamone G, Trevani A . Non-malignant leukocytes delay spontaneous B-CLL cell apoptosis. Leukemia. 2001; 15(12):1860-7. DOI: 10.1038/sj.leu.2402288. View

Lecuona E, Ridge K, Pesce L, Batlle D, Sznajder J . The GTP-binding protein RhoA mediates Na,K-ATPase exocytosis in alveolar epithelial cells. Mol Biol Cell. 2003; 14(9):3888-97. PMC: 196585. DOI: 10.1091/mbc.e02-12-0781. View

Glasow A, Prodromou N, Xu K, von Lindern M, Zelent A . Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. Blood. 2004; 105(1):341-9. DOI: 10.1182/blood-2004-03-1074. View

Norman J, PRICE L, Ridley A, Koffer A . The small GTP-binding proteins, Rac and Rho, regulate cytoskeletal organization and exocytosis in mast cells by parallel pathways. Mol Biol Cell. 1996; 7(9):1429-42. PMC: 275992. DOI: 10.1091/mbc.7.9.1429. View

Pastor-Anglada M, Casado F, Valdes R, Mata J, Molina M . Complex regulation of nucleoside transporter expression in epithelial and immune system cells. Mol Membr Biol. 2001; 18(1):81-5. DOI: 10.1080/096876800110033783. View

Yang L, Ostrowski J, Reczek P, Brown P . The retinoic acid receptor antagonist, BMS453, inhibits normal breast cell growth by inducing active TGFbeta and causing cell cycle arrest. Oncogene. 2001; 20(55):8025-35. DOI: 10.1038/sj.onc.1204911. View

Mercader J, Gomez-Angelats M, Del Santo B, Casado F, Felipe A, Pastor-Anglada M . Nucleoside uptake in rat liver parenchymal cells. Biochem J. 1996; 317 ( Pt 3):835-42. PMC: 1217560. DOI: 10.1042/bj3170835. View

Bennett J, Catovsky D, Daniel M, Flandrin G, GALTON D, Gralnick H . Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976; 33(4):451-8. DOI: 10.1111/j.1365-2141.1976.tb03563.x. View

10.

Chiorazzi N, Rai K, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med. 2005; 352(8):804-15. DOI: 10.1056/NEJMra041720. View

11.

Errasti-Murugarren E, Molina-Arcas M, Casado F, Pastor-Anglada M . A splice variant of the SLC28A3 gene encodes a novel human concentrative nucleoside transporter-3 (hCNT3) protein localized in the endoplasmic reticulum. FASEB J. 2008; 23(1):172-82. DOI: 10.1096/fj.08-113902. View

12.

AlSayed Y, Uddin S, Mahmud N, Lekmine F, Kalvakolanu D, Minucci S . Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to all-trans-retinoic acid. J Biol Chem. 2000; 276(6):4012-9. DOI: 10.1074/jbc.M007431200. View

13.

Bhowmick N, Ghiassi M, Bakin A, Aakre M, Lundquist C, Engel M . Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell. 2001; 12(1):27-36. PMC: 30565. DOI: 10.1091/mbc.12.1.27. View

14.

Dai X, Yamasaki K, Shirakata Y, Sayama K, Hashimoto K . All-trans-retinoic acid induces interleukin-8 via the nuclear factor-kappaB and p38 mitogen-activated protein kinase pathways in normal human keratinocytes. J Invest Dermatol. 2004; 123(6):1078-85. DOI: 10.1111/j.0022-202X.2004.23503.x. View

15.

Symons M, Rusk N . Control of vesicular trafficking by Rho GTPases. Curr Biol. 2003; 13(10):R409-18. DOI: 10.1016/s0960-9822(03)00324-5. View

16.

Molina-Arcas M, Bellosillo B, Casado F, Montserrat E, Gil J, Colomer D . Fludarabine uptake mechanisms in B-cell chronic lymphocytic leukemia. Blood. 2002; 101(6):2328-34. DOI: 10.1182/blood-2002-07-2236. View

17.

Flanagan S, Meckling K . All- trans-retinoic acid increases cytotoxicity of 1-beta-D-arabinofuranosylcytosine in NB4 cells. Cancer Chemother Pharmacol. 2003; 51(5):363-75. DOI: 10.1007/s00280-002-0561-0. View

18.

Pedersen I, Reed J . Microenvironmental interactions and survival of CLL B-cells. Leuk Lymphoma. 2004; 45(12):2365-72. DOI: 10.1080/10428190412331272703. View

19.

Nunes I, Kojima S, Rifkin D . Effects of endogenously activated transforming growth factor-beta on growth and differentiation of retinoic acid-treated HL-60 cells. Cancer Res. 1996; 56(3):495-9. View

20.

Maeda A, Amano M, Fukata Y, Kaibuchi K . Translocation of Na(+),K(+)-ATPase is induced by Rho small GTPase in renal epithelial cells. Biochem Biophys Res Commun. 2002; 297(5):1231-7. DOI: 10.1016/s0006-291x(02)02342-2. View