scholarly journals The MEK5/ERK5 Pathway in Health and Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7594
Author(s):  
Rupesh Paudel ◽  
Lorenza Fusi ◽  
Marc Schmidt
Keyword(s):  
Mechanical Stress ◽  
Fluid Shear Stress ◽  
Therapy Resistance ◽  
Escape Route ◽  
Resistance Pathway ◽  
Stress Response Pathway ◽  
Mitogen Activated Protein ◽  
Health And Disease ◽  
Potential Risks ◽  
And Oxidative Stress

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.

scholarly journals G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 672
Author(s):  
Richard A. Pepermans ◽  
Geetanjali Sharma ◽  
Eric R. Prossnitz
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Inflammatory Diseases ◽  
Therapy Resistance ◽  
Breast Cancers ◽  
Obesity And Diabetes ◽  
Therapeutic Value ◽  
Health And Disease ◽  
Multiple Cells ◽  
G Protein Coupled

Estrogen is involved in numerous physiological and pathophysiological systems. Its role in driving estrogen receptor-expressing breast cancers is well established, but it also has important roles in a number of other cancers, acting both on tumor cells directly as well as in the function of multiple cells of the tumor microenvironment, including fibroblasts, immune cells, and adipocytes, which can greatly impact carcinogenesis. One of its receptors, the G protein-coupled estrogen receptor (GPER), has gained much interest over the last decade in both health and disease. Increasing evidence shows that GPER contributes to clinically observed endocrine therapy resistance in breast cancer while also playing a complex role in a number of other cancers. Recent discoveries regarding the targeting of GPER in combination with immune checkpoint inhibition, particularly in melanoma, have led to the initiation of the first Phase I clinical trial for the GPER-selective agonist G-1. Furthermore, its functions in metabolism and corresponding pathophysiological states, such as obesity and diabetes, are becoming more evident and suggest additional therapeutic value in targeting GPER for both cancer and other diseases. Here, we highlight the roles of GPER in several cancers, as well as in metabolism and immune regulation, and discuss the therapeutic value of targeting this estrogen receptor as a potential treatment for cancer as well as contributing metabolic and inflammatory diseases and conditions.

scholarly journals HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3761
Author(s):  
Laura Hüser ◽  
Marianthi-Maria Kokkaleniou ◽  
Karol Granados ◽  
Jennifer Dworacek ◽  
Aniello Federico ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Clinical Success ◽  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Surface Expression ◽  
Therapy Resistance ◽  
Cell Surface Expression ◽  
Adaptive Resistance ◽  
Mitogen Activated Protein ◽  
Increased Sensitivity

Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 (SOX2) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.

Role of vasoactive peptides in high glucose-induced increased expression of Gαq/11 proteins and associated signaling in vascular smooth muscle cellsThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease.

2010 ◽  
Vol 88 (3) ◽  
pp. 331-340 ◽  
Author(s):  
Magda Descorbeth ◽  
Madhu B. Anand-Srivastava
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
High Glucose ◽  
Ang Ii ◽  
Vasoactive Peptides ◽  
Enhanced Production ◽  
Enhanced Expression ◽  
Health And Disease ◽  
And Oxidative Stress

We have recently shown that A10 vascular smooth muscle cells (VSMCs) exposed to high glucose exhibited enhanced expression of Gαq and PLCβ proteins. Since high glucose has been reported to increase the levels of vasoactive peptides and oxidative stress, the present study was undertaken to investigate the implication of angiotensin II (Ang II), endothelin (ET)-1, and oxidative stress in the high glucose-induced enhanced expression of Gαq/11 and PLCβ proteins and associated signaling in A10 VSMCs. The levels of Gαq, Gα11, PLCβ-1, and PLCβ-2 proteins, as determined by Western blotting, were significantly higher in A10 VSMCs exposed to high glucose than in control cells. The elevated levels were restored to control values by the antioxidant diphenyleneiodonium (DPI), as well as by the antagonist of Ang II AT1 receptor losartan and the antagonists of ETA and ETB receptors BQ123 and BQ788, respectively. In addition, ET-1-stimulated production of inositol trisphosphate (IP3), which was enhanced by high glucose, was also restored toward control levels by DPI. Furthermore, the enhanced production of superoxide anion (O2–), increased NADPH oxidase activity, and enhanced expression of p22phox and p47phox proteins induced by high glucose were restored to control levels by losartan, BQ123, and BQ788. These results suggest that through increased oxidative stress, high glucose-induced enhanced levels of endogenous Ang II and ET-1 may contribute to the increased levels of Gαq/11 and mediated signaling in A10 VSMCs.

Quercetin attenuates cyclooxygenase-2 expression in response to acute ureteral obstruction

2015 ◽  
Vol 308 (11) ◽  
pp. F1297-F1305 ◽  
Author(s):  
Inge Carlsen ◽  
Jørgen Frøkiær ◽  
Rikke Nørregaard
Keyword(s):  
Oxidative Stress ◽  
Mechanical Stress ◽  
Ureteral Obstruction ◽  
Naturally Occurring ◽  
Renal Inner Medulla ◽  
Cox 2 ◽  
And Oxidative Stress ◽  
Quercetin Treatment

Unilateral ureteral obstruction (UUO) is associated with increased hydrostatic pressure, inflammation, and oxidative stress in the renal parenchyma. Previous studies have demonstrated marked cyclooxygenase (COX)-2 induction in renal medullary interstitial cells (RMICs) in response to UUO. The aim of the present study was to evaluate the effect of quercetin, a naturally occurring antioxidant, on COX-2 induction in vivo and in vitro. Rats subjected to 24 h of UUO were treated intraperitoneally with quercetin (50 mg·kg−1·day−1). Quercetin partly prevented COX-2 induction in the renal inner medulla in response to UUO. Moreover, RMICs exposed to conditions associated with obstruction, inflammation (produced by IL-1β), oxidative stress (produced by H2O2), and mechanical stress (produced by stretch) showed increased COX-2 expression. Interestingly, quercetin reduced COX-2 induction in RMICs subjected to stretched. Similarly, PGE2 production was markedly increased in RMICs exposed to stretch and was reversed to control levels by quercetin treatment. Furthermore, stretch-induced phosphorylation of ERK1/2 was blocked by quercetin, and inhibition of ERK1/2 attenuated stretch-induced COX-2 induction in RMICs. These results indicate that quercetin attenuated the induction of COX-2 expression and activity in RMICs exposed to mechanical stress as a consequence of acute UUO and that the MAPK ERK1/2 pathway might be involved in this quercetin-mediated reduction in COX-2.

scholarly journals Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

2021 ◽  
Author(s):  
Abinaya Raghavan ◽  
Pooja Rao ◽  
Jiri Neuzil ◽  
Dean L. Pountney ◽  
Sangeeta Nath
Keyword(s):  
Oxidative Stress ◽  
Intercellular Communication ◽  
Rho Gtpases ◽  
Crucial Role ◽  
Oxygen Species ◽  
Health And Disease ◽  
Mitochondrial Heteroplasmy ◽  
Mediate Cell ◽  
Cellular Stresses ◽  
And Oxidative Stress

AbstractTunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

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