| RRC ID |
69045
|
| 著者 |
Cong B, Nakamura M, Sando Y, Kondo T, Ohsawa S, Igaki T.
|
| タイトル |
JNK and Yorkie drive tumor malignancy by inducing L-amino acid transporter 1 in Drosophila.
|
| ジャーナル |
PLoS Genet
|
| 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.
|
| 巻・号 |
17(11)
|
| ページ |
e1009893
|
| 公開日 |
2021-11-1
|
| DOI |
10.1371/journal.pgen.1009893
|
| PII |
PGENETICS-D-20-01337
|
| PMID |
34780467
|
| PMC |
PMC8629376
|
| MeSH |
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*
|
| IF |
5.175
|
| リソース情報 |
| ショウジョウバエ |
4236R-1
DGRC#140092 |
