Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis

Chen, Carolyn; Gubbiotti, Maria A.; Kapoor, Aastha; Han, Xianlin; Yu, Yanglei; Linhardt, Robert J.; Iozzo, Renato V.

doi:10.1016/j.matbio.2020.02.001

Cited by 28 publications

(24 citation statements)

References 103 publications

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“…1 B). We would like to note out that the observation that serum-starved cells synthesized low hyaluronan amounts could be due to autophagic clearance of HAS2 evoked by the nutrient deprivation, which is a novel mechanism for hyaluronan suppression recently demonstrated by Chen and colleagues [ 55 ]. As a consequence, the effect of salicylate on secreted hyaluronan from these cells is moderate.…”

Section: Discussionmentioning

confidence: 95%

Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells

Karalis

Chatzopoulos

Kondyli

et al. 2020

Matrix Biology Plus

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The oncogenic role of hyaluronan in several aspects of tumor biology has been well established. Recent studies by us and others suggest that inhibition of hyaluronan synthesis could represent an emerging therapeutic approach with significant clinical relevance in controlling different breast cancer subtypes, including triple-negative breast cancer. Epidemiological and preclinical studies have revealed the therapeutic potential of aspirin (acetyl salicylate), a classical anti-inflammatory drug, in patients with cancer. However, the underlying molecular mechanisms remain unknown. The present study demonstrates that salicylate, a break down product of aspirin in vivo, alters the organization of hyaluronan matrices by affecting the expression levels of hyaluronan synthesizing (HAS1, 2, 3) and degrading (HYAL-1, -2) enzymes, and that of hyaluronan receptor CD44. In particular, salicylate was found to potently activate AMPK, a kinase known to inhibit HAS2 activity, and caused a dose-dependent decrease of cell associated (intracellular and membrane-bound) as well as secreted hyaluronan, followed by the down-regulation of HAS2 and the induction of HYAL-2 and CD44 in metastatic breast cancer cells. These salicylate-mediated effects were associated with the redistribution of CD44 and actin cytoskeleton that resulted in a less motile cell phenotype. Interestingly, salicylate inhibited metastatic breast cancer cell proliferation and growth by inducing cell growth arrest without signs of apoptosis as evidenced by the substantial decrease of cyclin D1 protein and the absence of cleaved caspase-3, respectively. Collectively, our study offers a possible direction for the development of new matrix-based targeted treatments of metastatic breast cancer subtypes via inhibition of hyaluronan, a pro-angiogenic, pro-inflammatory and tumor promoting glycosaminoglycan.

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Section: Discussionmentioning

confidence: 95%

Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells

Karalis

Chatzopoulos

Kondyli

et al. 2020

Matrix Biology Plus

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“…During nutrient deprivation, AMPK is able to induce autophagy, 92-94 a lysosomal-dependent self-digestive process whereby cytoplasmic organelles, proteins, and even invading pathogens are hydrolyzed to recycle and generate nutrients to maintain cell homeostasis. A study of Chen et al demonstrated that the C-terminus part of perlecan (endorepellin) 95 induces HAS2 degradation via autophagy and suppresses extracellular HA deposition, 96 confirming that nutrient starvation negatively regulates HA synthesis. Interestingly, a recent paper reports that the activation of AMPK by salicylate affects the expression levels of HASes as well as the deposition of secreted and cell-associated HA, probably affecting HAS2 phosphorylation or salicylate glucuronidation and therefore, altering the availability of UDP-GlcUA.…”

Section: Role Of Ampk In Ha Metabolism and Cell Homeostasismentioning

confidence: 97%

Cell Energy Metabolism and Hyaluronan Synthesis

Caon

Parnigoni

Viola

et al. 2020

J Histochem Cytochem.

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Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine diphosphate (UDP)-glucuronic acid (UDP-GlcUA) and UDP- N-acetylglucosamine (UDP-GlcNAc) as substrates. The production of HA is mainly regulated by hyaluronan synthase 2 (HAS2), that can be controlled at different levels, from epigenetics to transcriptional and post-translational modifications. HA biosynthesis is an energy-consuming process and, along with HA catabolism, is strongly connected to the maintenance of metabolic homeostasis. The cytoplasmic pool of UDP-sugars is critical for HA synthesis. UDP-GlcNAc is an important nutrient sensor and serves as donor substrate for the O-GlcNAcylation of many cytosolic proteins, including HAS2. This post-translational modification stabilizes HAS2 in the membrane and increases HA production. Conversely, HAS2 can be phosphorylated by AMP activated protein kinase (AMPK), a master metabolic regulator activated by low ATP/AMP ratios, which inhibits HA secretion. Similarly, HAS2 expression and the deposition of HA within the pericellular coat are inhibited by sirtuin 1 (SIRT1), another important energetic sensor, confirming the tight connection between nutrients availability and HA metabolism.

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“…Regarding the HA network, treatment with salicylate results in AMPK activation, decreased HA production associated with decreased HAS2 levels and concurrent induction of hyaluronidase 2 in breast cancer cells. Notably, HAS2 can be reduced by autophagic degradation of the enzyme, thereby providing a novel way of counteracting pro-inflammatory and pro-angiogenic HA [ 95 ].…”

Section: Matrix Phenotypes Associated With Wound Healingmentioning

confidence: 99%

Complexity of matrix phenotypes

Iozzo

Theocharis

Neill

et al. 2020

Matrix Biology Plus

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The extracellular matrix is engaged in an ever-evolving and elegant ballet of dynamic reciprocity that directly and bi-directionally regulates cell behavior. Homeostatic and pathophysiological changes in cell-matrix signaling cascades manifest as complex matrix phenotypes. Indeed, the extracellular matrix can be implicated in virtually every known human disease, thus, making it the most critical and dynamic “organ” in the human body. The overall goal of this Special Issue is to provide an accurate and inclusive functional definition that addresses the inherent complexity of matrix phenotypes. This goal is summarily achieved via a corpus of expertly written articles, reviews and original research, focused at answering this question empirically and fundamentally via state-of-the-art methods and research strategies.

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Autophagic degradation of HAS2 in endothelial cells: A novel mechanism to regulate angiogenesis

Cited by 28 publications

References 103 publications

Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells

Salicylate suppresses the oncogenic hyaluronan network in metastatic breast cancer cells

Cell Energy Metabolism and Hyaluronan Synthesis

Complexity of matrix phenotypes

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