Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma
| Autor: | Nancy H. Colburn, Ya-Wen Wang, Yanlei Wang, Alyson R. Baker, Chi Wang, Jinpeng Liu, Jiang Zhu, Hsin-Sheng Yang, Qing Wang, Yong Dai |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Untranslated region Cancer Research Mice Nude Mechanistic Target of Rapamycin Complex 2 Biology Transfection mTORC2 Article 03 medical and health sciences Mice 0302 clinical medicine Growth factor receptor Cell Line Tumor Genetics Protein biosynthesis Animals Humans Genes Tumor Suppressor Neoplasm Invasiveness Kinase activity Molecular Biology Protein kinase B Adaptor Proteins Signal Transducing Mice Knockout Gene knockdown Akt RNA-Binding Proteins Translation (biology) HCT116 Cells invasion 030104 developmental biology Pdcd4 030220 oncology & carcinogenesis Protein Biosynthesis Colonic Neoplasms Eukaryotic Initiation Factor-4A Cancer research eIF4A Sin1 Apoptosis Regulatory Proteins Carrier Proteins HT29 Cells |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 |
| Popis: | Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently down-regulated in colorectal cancer and other cancers. In this study, we find that loss of Pdcd4 increases the activity of mammalian target of rapamycin complex 2 (mTORC2) and thereby upregulates Snail expression. Examining the components of mTORC2 showed that Pdcd4 knockdown increased the protein but not mRNA level of stress-activated-protein kinase interacting protein 1 (Sin1), which resulted from enhanced Sin1 translation. To understand how Pdcd4 regulates Sin1 translation, the SIN1 5’ untranslated region (5’UTR) was fused with luciferase reporter and named as 5’Sin1-Luc. Pdcd4 knockdown/knockout significantly increased the translation of 5’Sin1-Luc but not the control luciferase without the SIN1 5’UTR, suggesting that Sin1 5’UTR is necessary for Pdcd4 to inhibit Sin1 translation. Ectopic expression of wild type Pdcd4 and Pdcd4(157–469), a deletion mutant that binds to translation initiation factor 4A (eIF4A), sufficiently inhibited Sin1 translation, and thus suppressed mTORC2 kinase activity and invasion in colon tumor cells. By contrast, Pdcd4(157–469)(D253A,D418A), a mutant that does not bind to eIF4A, failed to inhibit Sin1 translation, and consequently failed to repress mTORC2 activity and invasion. In addition, directly inhibiting eIF4A with silvestrol significantly suppressed Sin1 translation and attenuated invasion. These results indicate that Pdcd4-inhibited Sin1 translation is through suppressing eIF4A, and functionally important for suppression of mTORC2 activity and invasion. Moreover, in colorectal cancer tissues, the Sin1 protein but not mRNA was significantly up-regulated while Pdcd4 protein was down-regulated, suggesting that loss of Pdcd4 might correlate with Sin1 protein level but not mRNA level in colorectal cancer patients. Taken together, our work reveals a novel mechanism by which Pdcd4 inhibits Sin1 translation to attenuatemTORC2 activity and thereby suppresses invasion. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink