TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity

Wennemers, Marloes; Bussink, Johan; Grebenchtchikov, Nicolaï; Sweep, Fred C.G.J.; Span, Paul N.

doi:10.1016/j.radonc.2011.05.057

Cited by 41 publications

(57 citation statements)

References 27 publications

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“…Likewise, high TRIB3 protein levels are associated with good prognosis in breast cancer patients. 36 In addition, TRIB3 is focally deleted in tumors of epithelial origin (tumorscape data set; Supplementary Table SI), thus supporting that loss or downregulation of TRIB3 is an event associated with human cancer. Nevertheless, other studies have found an upregulation of TRIB3 mRNA levels in human cancers.…”

Section: Discussionmentioning

confidence: 77%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumorsuppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis. Pseudokinases constitute a group of proteins that have a kinase-like domain that lacks at least one of the conserved catalytic residues. 1,2 Different studies have shown that some pseudokinases can exhibit low levels of kinase activity, while others have critical roles as activators of their specific targets. 1,2 Moreover, aberrant regulation of pseudokinases has been implicated in the etiology and progression of a variety of diseases, including cancer. 3 The Tribbles family of pseudokinases was first described in Drosophila as a negative regulator of cell division in early embryogenesis. [4][5][6][7] There are three mammalian Tribbles isoforms (Trib1, Trib2 and Trib3), homologs to the Drosophila tribbles proteins, and they all share a highly conserved central kinase-like domain, which lacks catalytic residues, and a 'tribbles specific' C-terminal domain, which has been proposed to participate in the binding to different Tribbles partners. 8 Tribbles pseudokinase-3 (TRIB3; also named TRB3, NIPK and SKIP3) has been proposed to interact with several proteins, including the transcription factors activating transcription factor 4 (ATF-4) and CHOP 9 as well as with several MAPKs. 10 TRIB3 has also been shown to interact and inhibit AKT, 11 which has been suggested to suppress insulin signaling. 11,12 In addition, administration of different anticancer agents promotes cancer cell death via TRIB3 upregulation and the subsequent inhibition of Akt. [13][14][15][16][17][18][19] However, the precise molecular basis of the regulation of Akt by TRIB3 and whether loss of this pseudokinase may contribute to cancer initiation and progression remains to be clarified.In this study, we investigated the effect of the genetic inactivation of TRIB3 in several cellular and animal models of cancer. Our findings indicate that genetic inhibition of TRIB3 enhances tumorigenesis and that this effect is due -at least primarily -to a selective inactivation of the transcription factor FOXO by the mammalian target of rapamycin complex 2 (mTORC2)/AKT axis. ResultsGenetic inhibition of TRIB3 facilitates oncogene transformation and enhances the tumorigenicity of cancer c...

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Section: Discussionmentioning

confidence: 77%

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

et al. 2014

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“…Some laboratories reported elevated TRIB3 mRNA levels which correlated with bad prognosis in colorectal cancer (46) and breast cancer patients (47). On the other hand, high TRIB3 protein levels have been associated with good prognosis sensitivity to radiotherapy in breast cancer patients (48). As TRIB3 is a very stable protein (49), the discrepancies observed between TRIB3 mRNA and protein levels in human breast cancer prognosis might be due to posttranslational modifications, still to be described, that might modulate the ability of TRIB3 to interact with other proteins that regulate tumor growth.…”

Section: Discussionmentioning

confidence: 99%

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

Erazo

Lorente

López-Plana

et al. 2016

Clinical Cancer Research

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Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development.Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database.Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARa and PPARg as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARa/g or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial.Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARa/g-TRIB3-AktmTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.

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“…In addition to NGF withdrawal, Trib3 is induced by a variety of cellular stresses relevant to neurons, including the unfolded protein response and ER stress, nutrient deprivation, anoxia and ethanol exposure. [20][21][22][23][24][25]27,28,30,36 Given this and Trib3's suppression of Akt signaling, it can be anticipated that Trib3 is a participant in, and therefore a potential target for treatment of, a variety of neurological disorders and insults.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 In addition to NGF deprivation, Trib3 mRNA is upregulated by stresses, including hypoxia, ER stress and 6-hydroxydopamine treatment. [20][21][22][23] The range of functions attributed to Trib3 include regulating glucose homeostasis, promoting tumor cell migration, suppressing adipocyte differentiation, inhibiting ER stress and either promoting or inhibiting cell death. [24][25][26] Trib3 is a pseudokinase with an inactive catalytic domain.…”

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confidence: 99%

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

2013

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The mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/ activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron death.

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TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity

Abstract: Whereas mRNA levels of TRIB3 are related with a poor prognosis, TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance.

Cited by 41 publications

References 27 publications

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation

The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

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