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

Abstract

Metabolic diseases like obesity, atherosclerosis and diabetes are frequently associated with increased risk of aggressive cancers. Although metabolic dysfunctions in normal cells are manifested due to defective signaling networks that control cellular homeostasis, malignant cells utilize these signaling networks for their increased survival, growth and metastasis. Despite decades of research, a common mechanistic link between these chronic pathologies is still not well delineated. Evidences show that the unfolded protein response (UPR) and the endoplasmic reticulum stress (ERS) pathways are often dysregulated in both metabolic diseases and cancer. The UPR also triggers coordinated signaling with both PI3K/AKT/mTOR and Autophagy pathways in order to promote stress-adaptive mechanisms. Whereas, uncontrolled UPR and the resultant ERS escalates cells towards metabolic dysfunctions and ultimately cell death. In this review, we will discuss findings that implicate a crucial role for the multifunctional ERS-induced protein, TRIB3. The 'pseudokinase' function of TRIB3 facilitates the inactivation of multiple transcription factors and signaling proteins. The MEK1 binding domain of TRIB3 enables it to deactivate multiple MAP-kinases. In addition, the COP1 motif of TRIB3 assists ubiquitination and proteasomal degradation of numerous TRIB3 associated proteins. The most well studied action of TRIB3 has been on the PI3K/AKT/mTOR pathway, where TRIB3-mediated inhibition of AKT phosphorylation decreases insulin signaling and cell survival. Conversely, cancer cells can either upregulate the AKT survival pathway by suppressing TRIB3 expression or alter TRIB3 localization to degrade differentiation inducing nuclear transcription factors such as C/EBPα and PPARγ. The gain-of-function Q84R polymorphism in TRIB3 is associated with increased risk of diabetes and atherosclerosis. TRIB3 acts as a crucial 'stress adjusting switch' that links homeostasis, metabolic disease and cancer; and is being actively investigated as a disease biomarker and therapeutic target.

Palmitate Conditions Macrophages for Enhanced Responses toward Inflammatory Stimuli via JNK Activation

“…Regarding the palmitate-mediated upregulation of TRIB3 gene expression, our results agree with the ability of palmitate to induce TRIB3 expression in human liver cells (58) and podocytes (59). TRIB3 is a pseudokinase that modulates many signaling cascades associated with endoplasmic reticulum stress, nutrient deficiency, and insulin resistance (60), and it that acts as a negative regulator The Journal of Immunology of NF-kB-dependent transcription (61). Because TRIB3 negatively regulates CCL2 expression in podocytes (59), it is tempting to speculate that palmitate-induce TRIB3 upregulation might underlie the negative effect that palmitate has on the basal and LPSinduced expression of CCL2 in human macrophages.…”

COX7AR is a Stress-inducible Mitochondrial COX Subunit that Promotes Breast Cancer Malignancy

“…Among these genes, 46 genes are involved in stress response, 25 genes are involved in cell proliferation, 26 genes are involved in locomotion, 26 genes are involved in apoptosis, 22 genes are involved in metabolism, and 10 genes are involved in cellular oxygen levels. Interestingly, the most upregulated gene, TRIB3 , is a disease-related gene that has been called a “stress adjusting switch” 18 .…”

BCAP31, a cancer/testis antigen-like protein, can act as a probe for non-small-cell lung cancer metastasis

“…As an ER chaperone, BCAP31 is thought to regulate protein activation and folding, and thus is essential to other ER proteins 43 . Dysfunction of this ER chaperone could lead to the accumulation of stress signals that activate the unfolded protein response (UPR), endoplasmic reticulum overload response (EOR), and caspase-12 induced pathway to re-establish protein balance in cells undergoing stress 44 . Otherwise, this could promote metastatic progression 45 .…”