Open AccessInhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma
Author(s) -
Cormerais Yann,
PagnuzziBoncompagni Marina,
Schrötter Sandra,
Giuliano Sandy,
Tambutté Eric,
Endou Hitoshi,
Wempe Michael F.,
Pagès Gilles,
Pouysségur Jacques,
Picco Vincent
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14176
Subject(s) - medulloblastoma , amino acid transporter , cancer research , mtorc1 , amino acid , biology , transporter , toxicity , pharmacology , solute carrier family , radiation therapy , cell culture , cell growth , homeostasis , medicine , biochemistry , microbiology and biotechnology , gene , apoptosis , genetics , pi3k/akt/mtor pathway
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.