Open AccessJNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila
Author(s) -
Bojie Cong,
Mitsuki Nakamura,
Yukari Sando,
Takefumi Kondo,
Seiji Ohsawa,
Tatsushi Igaki
Publication year - 2021
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1009893
Subject(s) - biology , rna interference , carcinogenesis , cancer research , downregulation and upregulation , cancer , transcriptome , gene , drosophila melanogaster , genetics , gene expression , rna
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 (Ras V12 /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 Ras V12 /scrib -/- tumors. Intriguingly, LAT1 inhibitory drugs did not suppress growth of bantam /rab5 -/- tumors and overexpression of bantam rendered Ras V12 /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.