Heparan sulfation is essential for the prevention of cellular senescence

Jung, Sun Ho; Lee, H. C.; Dong, Yu; Kim, B. C.; Park, S. M.; Lee, Y. S.; Park, H. J.; Ko, Young‐Gyu; Lee, J. S.

doi:10.1038/cdd.2015.107

Cited by 37 publications

(34 citation statements)

References 72 publications

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“…It was reported that depletion of PAPSS2 expression inhibits cell proliferation and induces senescence in liver cancer cells [40]. We found that knockdown of PAPSS2 reduces both cell proliferation and migration in breast cancer cells, suggesting that the decreased metastasis potential in vivo may be due to decrease in cell migration and proliferation.…”

Section: Discussionmentioning

confidence: 54%

Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis

et al. 2018

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The zinc finger protein Snail is a master regulator of epithelial-mesenchymal transition (EMT) and a strong inducer of tumor metastasis, yet the signal cascades triggered by Snail have not been completely revealed. Here, we report the discovery of the sulfation program that can be induced by Snail in breast cancer cells, and which plays an essential role in cell migration and metastasis. Specifically, Snail induces the expression of PAPSS2, a gene that encodes a rate-limiting enzyme in sulfation pathway, and VCAN, a gene that encodes the chondroitin sulfate proteoglycan Versican in multiple breast cancer cells. Depletion of PAPSS2 in MCF7 and MDA-MB-231 cells results in reduced cell migration, while overexpression of PAPSS2 promotes cell migration. Moreover, MDA-MB-231-shPAPSS2 cells display a significantly lower rate of lung metastasis and lower number of micrometastatic nodules in nude mice, and conversely, MDA-MB-231-PAPSS2 cells increase lung metastasis. Similarly, depletion of VCAN dampens the cell migration activity induced by Snail or PAPSS2 in MCF 10A cells. Moreover, PAPSS inhibitor sodium chlorate effectively decreases cell migration induced by Snail and PAPSS2. More importantly, the expression of Snail, PAPSS2, and VCAN is positively correlated in breast cancer tissues. Together, these findings are important for understanding the genetic programs that control tumor metastasis and may identify previously undetected therapeutic targets to treat metastatic disease.

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Section: Discussionmentioning

confidence: 54%

Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis

et al. 2018

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“…Activation of that pathway, as was shown in our study, may be blocked by Sulodexide. In another study heparin sulfation appeared to be essential for prevention of cellular senescence and that effect was linked with inhibition of p53/p21 pathway [30]. This may suggest that many beneficial effects of Sulodexide in clinical practice may be due to its antisenescent activity.…”

Section: Discussionmentioning

confidence: 99%

Sulodexide Slows Down the Senescence of Aortic Endothelial Cells Exposed to Serum from Patients with Peripheral Artery Diseases

Sosińska-Zawierucha

Maćkowiak

Staniszewski

et al. 2018

Cell Physiol Biochem

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Background/Aims: Aging of the arterial endothelial cells results in the appearance of their inflammatory phenotype, which may predispose patients to the acceleration of arteriosclerosis. We studied the effect of serum from patients with peripheral artery disease (PAD) on the senescence of human aortic endothelial cells (HAEC) and how that process is modulated by sulodexide. Methods: HAEC replicative aging in vitro was studied in the presence of 10% PAD-serum (PAD Group) or10%PAD serum and Sulodexide 0.5 LRU/mL (PAD-SUL group). In control group cells were cultured in medium supplemented with 10% fetal bovine serum. All studied parameters were evaluated at the beginning and at the end of the study, in all experimental groups. Population doubling time (PDT) was studied from the cells growth rate after repeated passages, and senescence-associated beta- galactosidase activity (SA-β gal activity) was measured with the fluorescence flow cytometry. Expression of IL6, vWF, p21 and p53 genes was measured with the real-time polymerase chain reaction (Real-Time PCR). Concentrations of IL6 and vWF were measured with the standard ELISA kits. Results: PAD serum accelerated the senescence of HAEC as reflected by increased, compared to control, expression of the IL6 gene (+43%, p<0.05) vWF gene (+443%, p<0.01), p21 gene (+ 124%, p<0.01) and p53 gene (+ 85%, p<0.01). Secretion of IL6 and vWF was higher in that group: + 101%, p<0.01 and + 78%, p<0.01, respectively, as compared to control. Also, SA-β gal activity was higher in the PAD group (+33%, p<0.05) than in the control group. In the PAD group PDT was longer (+108%, p<0.01) as compared to control. Simultaneous use of Sulodexide with PAD serum significantly reduced all the above described senescent changes in HAEC. Conclusions: PAD serum accelerates the aging of HAEC which may result in the faster progression of arteriosclerosis. Sulodexide reduces PAD induced senescence of HAEC, which results in lower inflammatory and thrombogenic activity of these cells.

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“…The function and health of the vascular network are regulated by the vascular endothelium releasing molecules that act in an autocrine and paracrine manner . In addition to the redox balance , nitric oxide (NO) is the most important mediator of normal endothelial function, through its powerful vasodilator action. NO is synthesized by the endothelial NO synthase (eNOS or NOS III) via the action of different neurohumoral mediators such as acetylcholine and circulating hormones .…”

Section: Endothelial Dysfunction and Ageing: The Role Of Nitric Oxidementioning

confidence: 99%

Arterial ageing: from endothelial dysfunction to vascular calcification

et al. 2017

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Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to ‘synthetic’ determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low‐level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well‐established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing‐related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed.

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Heparan sulfation is essential for the prevention of cellular senescence

Cited by 37 publications

References 72 publications

Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis

Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis

Sulodexide Slows Down the Senescence of Aortic Endothelial Cells Exposed to Serum from Patients with Peripheral Artery Diseases

Arterial ageing: from endothelial dysfunction to vascular calcification

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