title: 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.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
authors.forename: C
authors.initials: C
authors.lastname: Rosilio
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
authors.forename: M
authors.initials: M
authors.lastname: Nebout
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
authors.forename: V
authors.initials: V
authors.lastname: Imbert
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Griessinger
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France.
authors.forename: Z
authors.initials: Z
authors.lastname: Neffati
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Service d'Oncologie Pédiatrique, Hôpital de l'Archet, Nice, France.
authors.forename: J
authors.initials: J
authors.lastname: Benadiba
authors.affiliation: Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hagenbeek
authors.affiliation: Tytgat Institute of Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Spits
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratoire Central d'Anatomie et Cytologie Pathologiques, Hôpital de l'Archet, Nice, France.
authors.forename: J
authors.initials: J
authors.lastname: Reverso
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratoire Central d'Anatomie et Cytologie Pathologiques, Hôpital de l'Archet, Nice, France.
authors.forename: D
authors.initials: D
authors.lastname: Ambrosetti
authors.affiliation: Centre Hospitalier Universitaire de Nice, Laboratoire Central d'Anatomie et Cytologie Pathologiques, Hôpital de l'Archet, Nice, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Michiels
authors.affiliation: INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Complications hépatiques de l'obésité, Nice, France.
authors.forename: B
authors.initials: B
authors.lastname: Bailly-Maitre
authors.affiliation: 1] Department of Pharmacology and Toxicology, Kyorin University, Tokyo, Japan [2] J-Pharma, Co., Ltd, Yokohama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Endou
authors.affiliation: Medicinal Chemistry Core Facility, School of Pharmacy, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: 1] UMR INSERM U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Inflammation, Cancer, Cellules Souches Cancéreuses, Nice, France [2] Université de Nice-Sophia Antipolis, UFR Médecine, Faculté de Médecine, Nice, France [3] Centre Hospitalier Universitaire de Nice, Service d'Oncologie Pédiatrique, Hôpital de l'Archet, Nice, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Peyron
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D012333:RNA, Messenger