Ovarian Cancer G protein-Coupled Receptor 1 Is Involved in Acid-Induced Apoptosis of Endplate Chondrocytes in Intervertebral Discs

Yuan, Feng-Lai; Wang, Hui-Ren; Zhao, Mengnan; Yuan, Wei; Cao, Lu; Duan, Ping‐Guo; Jiang, Yuxin; Li, Xilei; Dong, Jian

doi:10.1002/jbmr.2030

Cited by 23 publications

(24 citation statements)

References 51 publications

(63 reference statements)

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“…Additionally, they demonstrated that only proliferating cells have the ability to translate an acidic pH e into gene transcription, suggesting that the acidic microenvironment provides a survival advantage to proliferating cancer cells over non-transformed cells (Glitsch, 2011). In contrast, Yuan et al have also recently shown that OGR1-mediated [Ca 2+ ] elevation induced apoptosis by activation of calcium-sensitive proteases and their downstream signaling molecules such as Bid, Bax, and caspase-3 in rat endplate chondrocytes (Yuan et al, 2013). Taken together, all these observations imply that transduction of the acid-sensing signal is highly context-dependent, leads to various phenotypes, and depends on the cell-specific genetic history and lineage.…”

Section: Ph Sensors In Plasma Membranementioning

confidence: 98%

pH sensing and regulation in cancer

2013

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Cells maintain intracellular pH (pHi) within a narrow range (7.1–7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H+-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.

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Section: Ph Sensors In Plasma Membranementioning

confidence: 98%

pH sensing and regulation in cancer

2013

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“…19,76,78,79 GPR68 activation by acidosis stimulates apoptosis in chondrocytes. 80 endocrine N/A Regulates inflammatory gene expression in insulin target tissues; insulin sensitivity is increased in GPR4-null mice. 83 increases insulin secretion in response to acidosis.…”

Section: Respiratorymentioning

confidence: 99%

“…GPR68 expression in rat endplate chondrocytes was found to induce apoptosis in response to acidosis, 80 which could reduce collagen production and lead to intervertebral disk degeneration.…”

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confidence: 99%

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin¹,

Justus²,

Krewson³

et al. 2015

CHC

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Protons (hydrogen ions) are the simplest form of ions universally produced by cellular metabolism including aerobic respiration and glycolysis. Export of protons out of cells by a number of acid transporters is essential to maintain a stable intracellular pH that is critical for normal cell function. Acid products in the tissue interstitium are removed by blood perfusion and excreted from the body through the respiratory and renal systems. However, the pH homeostasis in tissues is frequently disrupted in many pathophysiologic conditions such as in ischemic tissues and tumors where protons are overproduced and blood perfusion is compromised. Consequently, accumulation of protons causes acidosis in the affected tissue. Although acidosis has profound effects on cell function and disease progression, little is known about the molecular mechanisms by which cells sense and respond to acidotic stress. Recently a family of pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), has been identified and characterized. These GPCRs can be activated by extracellular acidic pH through the protonation of histidine residues of the receptors. Upon activation by acidosis the pH-sensing GPCRs can transduce several downstream G protein pathways such as the G s , G q/11 , and G 12/13 pathways to regulate cell behavior. Studies have revealed the biological roles of the pH-sensing GPCRs in the immune, cardiovascular, respiratory, renal, skeletal, endocrine, and nervous systems, as well as the involvement of these receptors in a variety of pathological conditions such as cancer, inflammation, pain, and cardiovascular disease. As GPCRs are important drug targets, small molecule modulators of the pH-sensing GPCRs are being developed and evaluated for potential therapeutic applications in disease treatment.

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“…Our previous study demonstrated that acid promoted apoptosis of rat endplate chondrocytes via the ovarian cancer G protein-coupled receptor 1 (OGR1) (52). Similarly, articular chondrocytes also underwent apoptosis due to the acidic microenvironment (53).…”

Section: Acidic Stressmentioning

confidence: 99%

Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism

Jiang

Yuan

Yin

et al. 2014

Connective Tissue Research

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Intervertebral discs comprise the largest avascular cartilaginous organ in the body, and its nutrient condition can be impaired by degeneration, aging and even metabolic disease. The unique microenvironment brings special stresses to various disc cell types, including nucleus pulposus cells, notochordal cells, annulus fibrosus cells and endplate chondrocytes. These cells experience nutrient starvation, acidic stress, hypoxic stress, hyperglycemic stress, osmotic stress and mechanical stress. Understanding the detailed responses and complex adaptive mechanisms of disc cells to various stresses might provide some clues to guide therapy for disc degeneration. By reviewing the published literatures describing disc cells under different hostile microenvironments, we conclude that these cells exhibit different responses to microenvironmental stresses with different mechanisms. Moreover, the interaction and combination of these stresses create a complex environment that synergistically increase or decrease influences on disc cells, compared with the effects of a single stress. Interestingly, most of these stresses activate autophagy, a self-protective mechanism by which dysfunctional protein and organelles are degraded. It is becoming clear that autophagy facilitates the cellular adaptation to stresses and might play a central role in regulating the adaptation of disc cells under stress. Therefore, autophagy modulation might be a potential therapeutic method to treat disc degeneration.

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Ovarian Cancer G protein-Coupled Receptor 1 Is Involved in Acid-Induced Apoptosis of Endplate Chondrocytes in Intervertebral Discs

Cited by 23 publications

References 51 publications

pH sensing and regulation in cancer

pH sensing and regulation in cancer

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism

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