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

Abstract

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.

Degradation of the Tumor Suppressor PDCD4 Is Impaired by the Suppression of p62/SQSTM1 and Autophagy

“…Previous studies have revealed the cell cycle inhibitory and apoptosis-inducing roles of PDCD4, so PDCD4 has been regarded as a tumor suppressor [9][10][11][12]. The downregulation of PDCD4 is observed in different types of cancer, such as colorectal carcinoma [13], prostate cancer [14], glioblastoma [15], lung cancer [16], and hepatocellular carcinoma [12]. Several mechanisms underlying the downregulation of PDCD4 have been reported.…”

c-Jun N-terminal kinase (JNK)–mediated induction of mSin1 expression and mTORC2 activation in mesenchymal cells during fibrosis

“…MCs isolated from fibrotic lung allografts demonstrated significantly higher mSin1 expression compared with MCs isolated from normal lung allografts. Increased expression of mSin1 has been linked to metastatic and activated behavior in cancer cells (31)(32)(33). mSin1 was shown to be up-regulated in non-small-cell lung cancer (31) as well as in metastatic carcinoma of the colon (33) and the liver (32), with mSin1 suppression inhibiting proliferation, migration, and invasion rates.…”

Role of PDCD4 in inflammation and tumors: a double-edged sword

“…主调节基因肝X受体-α(liver X receptor-α, LXR-α)的表 达, 促进肥胖所导致慢性炎症以及胰岛素抵抗 [48] . 最 近Wang等人 [49] 的研究证明, 在结肠癌模型中PDCD4…”