TRIB3 enhances cell viability during glucose deprivation in HEK293-derived cells by upregulating IGFBP2, a novel nutrient deficiency survival factor

Abstract

Glucose deprivation occurs in several human diseases, including infarctions and solid tumors, and leads to cell death. In this article, we investigate the role of the pseudokinase Tribbles homolog 3 (TRIB3) in the cellular stress response to glucose starvation using cell lines derived from HEK293, which is highly glycolytic under standard conditions. Our results show that TRIB3 mRNA and protein levels are strongly upregulated in glucose-deprived cells via the induction of activating transcription factor 4 (ATF4) by the endoplasmic reticulum (ER) stress sensor kinase PERK. Cell survival in glucose-deficient conditions is enhanced by TRIB3 overexpression and reduced by TRIB3 knockdown. Genome-wide gene expression profiling uncovered approximately 40 glucose deprivation-responsive genes that are affected by TRIB3, including several genes involved in signaling processes and metabolism. Based on transcription factor motif analysis, the majority of TRIB3-downregulated genes are target genes of ATF4, which TRIB3 is known to inhibit. The gene most substantially upregulated by TRIB3 is insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 mRNA and protein levels are downregulated in cells subjected to glucose deprivation, and reduced IGFBP2 expression aggravates cell death during glucose deficiency, while overexpression of IGFBP2 prolongs cell survival. Moreover, IGFBP2 silencing abrogates the pro-survival effect of TRIB3. Since TRIB3 augments IGFBP2 expression in glucose-starved cells, the data indicate that IGFBP2 contributes to the attenuation of cell death by TRIB3. These results implicate TRIB3 and IGFBP2, both of which are known to be overexpressed in several types of cancers, as pro-survival modulators of cell viability in nutrient-deficient microenvironments.

Overexpression of TRIB3 promotes angiogenesis in human gastric cancer

“…Currently, three mammalian homologs of the tribbles gene are known. One of these, TRIB3, plays an important role in multiple signaling pathways, coordinating crucial cellular processes such as apoptosis, glucose and lipid metabolism, adipocyte differentiation, and cell stress (15,(24)(25)(26)(27). TRIB3 is overexpressed in many cancers, but whether TRIB3 is upregulated in GC has not been reported previously.…”

Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer

“…Over-expression of TRIB3 in skeletal muscle cells can block GLUT4 translocation and suppress insulin-stimulated glucose uptake [187]. Indeed, it is worth mentioning that the endothelial dysfunctions and dyslipidemia observed with the clinically approved HIV-1 protease inhibitors like Nelfinavir has also been linked to the inhibition of both proteasome activity and glucose transport, both by us [207,208] [64,88,95,115,121]. Interestingly however, a recent clinical finding by Boden et al (2014) suggested that insulin resistance is actually associated with diminished ERS responses in adipose tissue of healthy and diabetic subjects [213].…”

Pharmacological or TRIB3-Mediated Suppression of ATF4 Transcriptional Activity Promotes Hepatoma Cell Resistance to Proteasome Inhibitor Bortezomib

“…Immunoblotting was carried out as described previously [ 76 ]. The following antibodies were used: mouse anti-Flag M2 monoclonal antibody (1:1500 dilution; Sigma #F3165), rabbit anti-ATF4 polyclonal antibody (1:5000 dilution; Santa Cruz Biotechnology sc-200, Santa Cruz, CA, USA) and rabbit anti-β-Tubulin polyclonal antibody (1:2500 dilution; Abcam #ab6046, Cambridge, UK).…”