The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control

Abstract

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively studied in cancers. In this review, we evaluate the current literature regarding the regulation and the function of TXNIP, highlighting its emerging role in modulating signaling between different cell types within the TME. We then assess current and future translational opportunities and the associated challenges in this area. An improved understanding of the functions and mechanisms of TXNIP in cancers may enhance its suitability as a therapeutic target.

Fig. 1. ER stress-mediated TXNIP regulation mainly depends on PERK and/or IRE-1a signaling pathways.

Both PERK and IRE-1 are required for TXNIP induction in ER-stress-induced β-cell death [31]. Notably, PERK on its own can also regulate TXNIP [57]. IRE1α and its downstream effector XBP1 are also shown to be responsible for TXNIP-induced mitochondrial dysfunction, without involvement of PERK signaling [56]. Recently, IRE1α-microRNA signaling axis (miR-17) has been described to control TXNIP expression [55].

Fig. 2. TXNIP is regulated by diverse factors and the regulation is bi-directional.

TXNIP expression is regulated by a variety of different signaling pathways, including microRNAs, oncogenes and TSGs, cytokines and growth factors, endoplasmic reticulum and some specific environmental conditions (e.g. hypoxia). Additionally, TXNIP also regulates these pathways as part of a feedback loop to attenuate or amplify signaling. For example, oncogenes, including Kras, HER2 and c-Myc, induce TXNIP expression, while TXNIP can regulate the expression of p53 and PTEN. Moreover, HIF-1a and TXNIP can regulate each other under different conditions.

Fig. 3. TXNIP is closely involved in various biological processes.

a TXNIP can positively or negatively regulate oxidative stress via binding with either Trx or p53; b the activation of TXNIP leads to tumor suppression by affecting cell differentiation, cell stemness and cell death (such as apoptosis, autophagy, and senescence); c TXNIP mediates drug-induced cell death via ROS-dependent/- independent pathways; d TXNIP impacts on cellular metabolism, transforming cells from glycolytic to reliant on oxidative phosphorylation, by regulating the expression of GLUT1/4; e TXNIP increases the expression of VEGFA, PDGF, and ANG2.

Fig. 4. TXNIP plays important roles in both innate and adaptive immune regulations.

Schematic summarising the impacts of TXNIP on different arms of the immune system. TXNIP can maintain the survival and promote the activation of NK and dendritic cells (DC), leading to increase cytotoxicity [148, 151]. Meanwhile, TXNIP facilitates the differentiation of monocytes to M2 macrophages, creating a pro-tumoral microenvironment [154]. Moreover, TXNIP is involved in the development of various T and B cell subsets. It is essential in maintaining the identity of Tregs [163], while inhibiting the formation and activation of memory T cells and CD8⁺ T cells [156, 159]. Through inhibition of BCL-6, TXNIP can promote the formation of the germinal center [168].

Fig. 5. Cellular metabolism contributes to the plasticity of Tregs.

The expression of TXNIP in Tregs determines their metabolic state. Low expression of TXNIP in Tregs promotes glycolysis, facilitating Th17 inflammation, whilst high TXNIP expression in Tregs switches the cells towards OXPHOS, helping to maintain suppressive function.