L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

Abstract	The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.
Authors	C Rosilio, M Nebout, V Imbert, E Griessinger, Z Neffati, J Benadiba, T Hagenbeek, H Spits, J Reverso, D Ambrosetti, J-F Michiels, B Bailly-Maitre, H Endou, M F Wempe, J-F Peyron
Journal	Leukemia (Leukemia) Vol. 29 Issue 6 Pg. 1253-66 (Jun 2015) ISSN: 1476-5551 [Electronic] England
PMID	25482130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	RNA, Messenger
Topics	Animals Apoptosis Blotting, Western Breast Neoplasms (drug therapy, enzymology, pathology) Cell Adhesion Cell Cycle Cell Movement Cell Proliferation Female Flow Cytometry Fluorescent Antibody Technique Humans Immunoenzyme Techniques Mice Mice, Inbred BALB C Mice, Nude RNA, Messenger (genetics) Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Xenograft Model Antitumor Assays

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