PMID- 28692058 OWN - NLM STAT- MEDLINE DCOM- 20171201 LR - 20220318 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 36 IP - 45 DP - 2017 Nov 9 TI - Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. PG - 6225-6234 LID - 10.1038/onc.2017.228 [doi] AB - Programmed cell death 4 (Pdcd4), a tumor invasion suppressor, is frequently downregulated 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 upregulated while Pdcd4 protein was downregulated, 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. FAU - Wang, Q AU - Wang Q AD - Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, USA. FAU - Zhu, J AU - Zhu J AD - Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China. FAU - Wang, Y-W AU - Wang YW AD - Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China. FAU - Dai, Y AU - Dai Y AD - Department of Colorectal and Anal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China. FAU - Wang, Y-L AU - Wang YL AD - Department of Colorectal and Anal Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China. FAU - Wang, C AU - Wang C AD - Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA. AD - Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA. FAU - Liu, J AU - Liu J AD - Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA. FAU - Baker, A AU - Baker A AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. FAU - Colburn, N H AU - Colburn NH AD - Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. FAU - Yang, H-S AU - Yang HS AD - Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, USA. AD - Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA. LA - eng GR - P30 CA177558/CA/NCI NIH HHS/United States GR - R01 CA129015/CA/NCI NIH HHS/United States GR - R03 CA187839/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20170710 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Carrier Proteins) RN - 0 (MAPKAP1 protein, human) RN - 0 (PDCD4 protein, human) RN - 0 (Pdcd4 protein, mouse) RN - 0 (RNA-Binding Proteins) RN - 0 (stress-activated protein kinase-interacting protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.7.- (Eukaryotic Initiation Factor-4A) SB - IM MH - Adaptor Proteins, Signal Transducing/antagonists & inhibitors/*genetics/metabolism MH - Animals MH - Apoptosis Regulatory Proteins/*genetics/metabolism MH - Carrier Proteins/antagonists & inhibitors/*genetics/metabolism MH - Cell Line, Tumor MH - Colonic Neoplasms/*genetics/metabolism/pathology MH - Eukaryotic Initiation Factor-4A/metabolism MH - Genes, Tumor Suppressor MH - HCT116 Cells MH - HT29 Cells MH - Humans MH - Mechanistic Target of Rapamycin Complex 2/metabolism MH - Mice MH - Mice, Knockout MH - Mice, Nude MH - Neoplasm Invasiveness MH - Protein Biosynthesis MH - RNA-Binding Proteins/*genetics/metabolism MH - Transfection PMC - PMC5680133 MID - NIHMS881383 COIS- CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. EDAT- 2017/07/12 06:00 MHDA- 2017/12/02 06:00 PMCR- 2018/01/10 CRDT- 2017/07/11 06:00 PHST- 2017/03/01 00:00 [received] PHST- 2017/05/22 00:00 [revised] PHST- 2017/06/01 00:00 [accepted] PHST- 2017/07/12 06:00 [pubmed] PHST- 2017/12/02 06:00 [medline] PHST- 2017/07/11 06:00 [entrez] PHST- 2018/01/10 00:00 [pmc-release] AID - onc2017228 [pii] AID - 10.1038/onc.2017.228 [doi] PST - ppublish SO - Oncogene. 2017 Nov 9;36(45):6225-6234. doi: 10.1038/onc.2017.228. Epub 2017 Jul 10.