Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer

Taneja, Sakshi; Vetter, Stefan; Leclerc, Estelle

doi:10.3390/ijms22158153

Cited by 14 publications

(7 citation statements)

References 222 publications

(276 reference statements)

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“…RAGE was bound by several ligands which activate three main signaling pathways including JAK/STAT, PI3K/AKT, and MAPK/ERK [ 20 ]. The HMGB1 and RAGE ligation activates EMT phenomenon and induces tumor growth in breast cancer [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells

et al. 2022

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Background High-mobility group box 1 (HMGB1) is increased in breast cancer cells as the result of exposure to the secreted substances from cancer-associated fibroblasts and plays a crucial role in cancer progression and drug resistance. Its effect, however, on the expression of programmed death ligand 1 (PD-L1) in breast cancer cells has not been investigated. This study aimed to investigate the mechanism of HMGB1 through receptors for advanced glycation end products (RAGE) on cell migration/invasion and PD-L1 expression in breast cancer cells. Methods A 3-dimensional (3-D) migration and invasion assay and Western blotting analysis to evaluate the function and the mechanism under recombinant HMGB1 (rHMGB1) treatment with knockdown of RAGE using shRAGE and PI3K/AKT inhibitors was performed. Results The results revealed that rHMGB1 induced MDA-MB-231 cell migration and invasion. The knockdown of RAGE using shRAGE and PI3K/AKT inhibitors attenuated 3-D migration and invasion in response to rHMGB1 compared to mock cells. PD-L1 up-regulation was observed in both parental MDA-MB-231 (P) and MDA-MB-231 metastasis to bone marrow (BM) cells treated with rHMGB1, and these effects were alleviated in RAGE-knock down (KD) breast cancer cells as well as in PI3K/AKT inhibitor-treated cells. Conclusions Collectively, these findings indicate that HMGB1-RAGE through PI3K/AKT signaling promotes not only breast cancer cell invasion but also PD-L1 expression which leads to the destruction of the effector T cells. The attenuating HMGB1-RAGE-PI3K/AKT pathway may help to attenuate breast cancer cell aggressive phenotypes.

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Section: Discussionmentioning

confidence: 99%

HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells

et al. 2022

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“…However, the connection between hypoxia and a presumed increase in the appearance of advanced glycation end products in adipocytes remains unclear. (While we must note that hypoxia increases AGE production, most of that research has focused on tumor cells [ 69 , 70 ]). In any case, hypoxia-mediated damage to hypertrophied adipocytes seems plausible, and AGEs released from damaged cells could ligand with RAGE on neighboring cells and trigger NF-κB activation.…”

Section: Activators Of Canonical Nf-κb Signaling In Adipocytesmentioning

confidence: 99%

On the Immunometabolic Role of NF-κB in Adipocytes

Griffin

2022

Immunometabolism

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Two decades of research have established that Nuclear Factor-κB (NF-κB) signaling plays a critical role in reprogramming the fat cell transcriptome towards inflammation in response to overnutrition and metabolic stress. Several groups have suggested that inhibition of NF-κB signaling could have metabolic benefits for obesity-associated adipose tissue inflammation. However, two significant problems arise with this approach. The first is how to deliver general NF-κB inhibitors into adipocytes without allowing these compounds to disrupt normal functioning in cells of the immune system. The second issue is that general inhibition of canonical NF-κB signaling in adipocytes will likely lead to a massive increase in adipocyte apoptosis under conditions of metabolic stress, leading full circle into a secondary inflammation (However, this problem may not be true for non-canonical NF-κB signaling.). This review will focus on the research that has examined canonical and non-canonical NF-κB signaling in adipocytes, focusing on genetic studies that examine loss-of-function of NF-κB specifically in fat cells. Although the development of general inhibitors of canonical NF-κB signaling seems unlikely to succeed in alleviating adipose tissue inflammation in humans, the door remains open for more targeted therapeutics. In principle, these would include compounds that interrogate NF-κB DNA binding, protein-protein interactions, or post-translational modifications that partition NF-κB activity towards some genes and away from others in adipocytes. I also discuss the possibility for inhibitors of non-canonical NF-κB signaling to realize success in mitigating fat cell dysfunction in obesity. To plant the seeds for such approaches, much biochemical “digging” in adipocytes remains; this includes identifying—in an unbiased manner–NF-κB direct and indirect targets, genomic DNA binding sites for all five NF-κB subunits, NF-κB protein-protein interactions, and post-translational modifications of NF-κB in fat cells.

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“…Disturbances in intracellular calcium homeostasis are a hallmark of hypoxia, linked to HIF-1α expression and stabilization [ 179 ]. Hypoxia-mediated cell damage, as well as the activation of immune cells by inflammatory signals, allows the release of S100 proteins to the extracellular space as damage-associated molecular pattern (DAMP) molecules, also known as alarmins, and then they can be recognized by and activating RAGE-mediated signaling [ 22 , 23 , 180 ].…”

Section: Metabolic Reprogrammingmentioning

confidence: 99%

“…Soon afterward its discovery, the binding capacity of RAGE was found to be extended to other ligands, beyond AGEs, such as the alarmin, high mobility group box 1 (HMGB1), and members of the S-100 calgranulins family. These molecules are abundant in the TME of most solid tumors, thus increasing the complexity of intracellular signaling networks involving RAGE [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

The RAGE/multiligand axis: a new actor in tumor biology

et al. 2022

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The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.

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Hypoxia and the Receptor for Advanced Glycation End Products (RAGE) Signaling in Cancer

Cited by 14 publications

References 222 publications

HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells

HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells

On the Immunometabolic Role of NF-κB in Adipocytes

The RAGE/multiligand axis: a new actor in tumor biology

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