JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila

Cong, B., Nakamura, M., Sando, Y., Kondo, T., Ohsawa, S. and Igaki, T. (2021) JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila. PLoS Genetics, 17(11), e1009893. (doi: 10.1371/journal.pgen.1009893) (PMID:34780467) (PMCID:PMC8629376)

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Abstract

Identifying a common oncogenesis pathway among tumors with different oncogenic mutations is critical for developing anti-cancer strategies. Here, we performed transcriptome analyses on two different models of Drosophila malignant tumors caused by Ras activation with cell polarity defects (RasV12/scrib-/-) or by microRNA bantam overexpression with endocytic defects (bantam/rab5-/-), followed by an RNAi screen for genes commonly essential for tumor growth and malignancy. We identified that Juvenile hormone Inducible-21 (JhI-21), a Drosophila homolog of the L-amino acid transporter 1 (LAT1), is upregulated in these malignant tumors with different oncogenic mutations and knocking down of JhI-21 strongly blocked their growth and invasion. JhI-21 expression was induced by simultaneous activation of c-Jun N-terminal kinase (JNK) and Yorkie (Yki) in these tumors and thereby contributed to tumor growth and progression by activating the mTOR-S6 pathway. Pharmacological inhibition of LAT1 activity in Drosophila larvae significantly suppressed growth of RasV12/scrib-/- tumors. Intriguingly, LAT1 inhibitory drugs did not suppress growth of bantam/rab5-/- tumors and overexpression of bantam rendered RasV12/scrib-/- tumors unresponsive to LAT1 inhibitors. Further analyses with RNA sequencing of bantam-expressing clones followed by an RNAi screen suggested that bantam induces drug resistance against LAT1 inhibitors via downregulation of the TMEM135-like gene CG31157. Our observations unveil an evolutionarily conserved role of LAT1 induction in driving Drosophila tumor malignancy and provide a powerful genetic model for studying cancer progression and drug resistance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cong, Mr Bojie
Creator Roles:
Cong, B.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review and editing
Authors: Cong, B., Nakamura, M., Sando, Y., Kondo, T., Ohsawa, S., and Igaki, T.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7404
ISSN (Online):1553-7404
Published Online:15 November 2021
Copyright Holders:Copyright © 2021 Cong et al.
First Published:First published in PLoS Genetics 17(11): e1009893
Publisher Policy:Reproduced under a Creative Commons License

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