Inhibition of the amino-acid transporter LAT1 demonstrates anti-neoplastic activity in medulloblastoma

J Cell Mol Med. 2019 Apr;23(4):2711-2718. doi: 10.1111/jcmm.14176. Epub 2019 Feb 19.

Abstract

Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.

Keywords: ATF4; GCN2; amino acid transport; mTORC1; medulloblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Benzoxazoles / pharmacology*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cerebellar Neoplasms / drug therapy
  • Cerebellar Neoplasms / genetics
  • Cerebellar Neoplasms / metabolism
  • Cerebellar Neoplasms / pathology
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Child
  • Embryo, Mammalian
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Large Neutral Amino Acid-Transporter 1 / genetics*
  • Large Neutral Amino Acid-Transporter 1 / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Medulloblastoma / drug therapy
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism
  • Medulloblastoma / pathology
  • Mice
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Organ Specificity
  • Primary Cell Culture
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Tyrosine / analogs & derivatives*
  • Tyrosine / pharmacology

Substances

  • 2-amino-3-(4-((5-amino-2-phenylbenzo(d)oxazol-7-yl)methoxy)-3,5-dichlorophenyl)propanoic acid
  • ATF4 protein, human
  • Antineoplastic Agents
  • Benzoxazoles
  • Large Neutral Amino Acid-Transporter 1
  • SLC7A5 protein, human
  • Activating Transcription Factor 4
  • Tyrosine
  • EIF2AK4 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases