Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway

Abstract

Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly-conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5'-terminal oligopyrimidine tract (5'-TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two-and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors. Polysome profiling and mRNA quantification indicate that these effects occur at the level of mRNA translation. Blocking this pathway upstream of mTOR complex 1 (mTORC1) by inhibiting Akt also prevented increases in TCTP levels in both HeLa and HT29 colon cancer cells, whereas knockout of TSC2, a negative regulator of mTORC1, led to derepression of TCTP synthesis under serum starvation. Overexpression of eIF4E enhanced the polysomal association of the TCTP mRNA, although it did not protect its translation from inhibition by rapamycin. Conversely, expression of a constitutively-active mutant of the eIF4E inhibitor 4E-BP1, which is normally inactivated by mTORC1, inhibited of TCTP mRNA translation in HEK293 cells. Our results demonstrate that TCTP mRNA translation is regulated by signalling through the PI3-K/Akt/mTORC1 pathway. This explains why TCTP levels are frequently increased in cancers, since mTORC1 signalling is hyperactive in ~80% of tumours.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Recently, we (Bommer et al 2017) and a Chinese group (Xiao et al 2016) demonstrated that indeed TCTP levels (assessed by immunohistochemistry) increase early in CRC, already at the adenoma stage. This is consistent with our finding that during growthinduction of both HeLa cells and HT29 colon cancer cells, TCTP synthesis is translationally up-regulated through the PI3K/Akt/mTORC1 signalling pathway (Bommer et al 2015), given the earlier observation that this pathway is activated early in the development of colorectal cancer (Zhang et al 2009). Epithelial-to-mesenchymal transition (EMT) of cancer cells is a crucial step in the development of invasiveness and metastasis of tumours.…”

“…Typically, we observed a four-fold increase of TCTP levels after serum-stimulation of mammalian cells (Bommer et al 2002(Bommer et al , 2015. The involvement of TCTP in cellular growth regulation is documented in various settings.…”

“…The 5 0 -TOP motif is a hallmark for a specific group of mRNAs that are under translational control through the mTOR complex 1 (mTORC1) signalling pathway (Meyuhas and Kahan 2015;Yamashita et al 2008). We have recently demonstrated that growth induction of TCTP expression is indeed regulated through this pathway (Bommer et al 2015).…”

“…(3) TCTP levels are also translationally regulated through the PI3-kinase/Akt/mTORC1 signalling pathway (Bommer et al 2015). Since this pathway is targeted by p53, through induction of its negative effectors PTEN and TSC2 (Feng et al 2007b), this implies that p53 also interferes with TCTP synthesis at the translational level.…”

“…This group of mRNAs largely comprises those mRNAs coding for components of the translational apparatus, in particular ribosomal proteins and translation factors (Meyuhas and Kahan 2015;Meyuhas 2000). The observations that the mRNA of TCTP also bears a 5 0 -TOP (Yamashita et al 2008;Meyuhas 2000) and is regulated through the mTORC1 pathway (Bommer et al 2015) would suggest that TCTP also participates in the activities (or regulation) of the translational machinery. In fact, as early as 2003, the Telerman group identified translation elongation factor eEF1A and its guanine nucleotide exchange factor eEF1Bβ as TCTP-interacting partners (Cans et al 2003).…”