Abstract
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.
Document Type
Article
Publication Date
11-9-2017
Digital Object Identifier (DOI)
https://doi.org/10.1038/onc.2017.228
Funding Information
This work was supported by the NIH/NCI grant to H.-S. Yang (R01CA129015 and R03CA187839), NCI/NIH center core support grant to C. Wang (P30CA177558) and National Natural Science Foundation of China grant to J. Zhu (81402192). The Flow Cytometry facility is supported in part by NCI Center Core Support Grant (P30CA177558).
Related Content
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Repository Citation
Wang, Qing; Zhu, Jiang; Wang, Ya-Wen; Dai, Yong; Wang, Yanlei; Wang, Chi; Liu, Jinpeng; Baker, Alyson; Colburn, Nancy H.; and Yang, Hsin-Sheng, "Tumor Suppressor Pdcd4 Attenuates Sin1 Translation to Inhibit Invasion in Colon Carcinoma" (2017). Toxicology and Cancer Biology Faculty Publications. 84.
https://uknowledge.uky.edu/toxicology_facpub/84
Supplementary Figure S1
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Supplementary Table S1
Notes/Citation Information
Published in Oncogene, v. 36, issue 45, p. 6225-6234.
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved
The copyright holder has granted the permission for posting the article here.
This is a post-peer-review, pre-copyedit version of an article published in Oncogene. The final authenticated version is available online at: https://doi.org/10.1038/onc.2017.228.