Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma

Q. Wang, J. Zhu, Y. W. Wang, Y. Dai, Y. L. Wang, C. Wang, J. Liu, A. Baker, N. H. Colburn, H. S. Yang

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Pages (from-to)6225-62354
Number of pages56130
JournalOncogene
Volume36
Issue number45
DOIs
StatePublished - Nov 9 2017

Bibliographical note

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma'. Together they form a unique fingerprint.

Cite this