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

PLoS Genet. 2021 Nov 15;17(11):e1009893. doi: 10.1371/journal.pgen.1009893. eCollection 2021 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / antagonists & inhibitors
  • Amino Acid Transport Systems / genetics
  • Amino Acid Transport Systems / metabolism*
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / pathology*
  • Drosophila
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drug Resistance, Neoplasm*
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism*
  • MicroRNAs / genetics
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / pathology
  • RNA Interference
  • Signal Transduction
  • Up-Regulation
  • YAP-Signaling Proteins / genetics
  • YAP-Signaling Proteins / metabolism*

Substances

  • Amino Acid Transport Systems
  • Drosophila Proteins
  • JhI-21 protein, Drosophila
  • MicroRNAs
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • bantam microRNA, Drosophila
  • MAP Kinase Kinase 4

Grants and funding

This work was supported by Grant-in-Aid for Scientific Research (A) (Grant No. 20H00515) to T.I, Japan Agency for Medical Research and Development (Project for Elucidating and Controlling Mechanisms of Aging and Longevity; Grant No. 21gm5010001) to T.I, Grant-in-Aid for Scientific Research on Innovative Areas (Grant No. 20H05320) to T.I, Grant-in-Aid for Transformative Research Areas A (Grant No. 20H05945 and 21H05284) to S.O and T.I, JST Moonshot R&D (Grant No. JPMJMS2022) to S.O, the Naito Foundation to S.O and T.I, the Takeda Science Foundation to S.O and T.I, Toray Science Foundation to S.O, and MSD Life Science Foundation to S.O. B.C was supported by JSPS Research Fellowships for Young Scientists. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.