Nuclear transport of galectin-3 and its therapeutic implications

Funasaka, Tatsuyoshi; Raz, Avraham; Nangia‐Makker, Pratima

doi:10.1016/j.semcancer.2014.03.004

Cited by 69 publications

(58 citation statements)

References 149 publications

(165 reference statements)

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“…The action of Gal-3 is mediated by intracellular Gal-3, especially in the nucleus, or secreted Gal-3 [21]. Secreted Gal-3 regulates cell adhesion and migration through cell-cell and cell-extracellular matrix interactions [16,22].…”

Section: Discussionmentioning

confidence: 99%

Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

Zhang

Zeng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Vascular muscularity is a key event in vessel remodeling during pulmonary artery hypertension (PAH). Endothelial-mesenchymal transdifferentiation (EndMT) has been increasingly reported to play a role in disease occurrence. Galectin-3, a carbohydrate-binding protein regulates cell proliferation, differentiation, migration and neovascularization. However, whether galectin-3 controls endothelial cell transdifferentiation during the development of PAH is unknown. Methods: Rats were exposed to normoxic or hypoxic conditions (fraction of inspired O₂ 0.10) for 21 d to establish PAH models. Hemodynamic changes were evaluated through surgery of the right jugular vein and ultrasound biomicroscopy inviVue. And vessel pathological alterations were detected by H&E staining. Galectin-3 (Gal-3)-induced pulmonary artery endothelium cell (PAEC) dynamic alterations were measured by MTT assays, Cell immunofluorescence, Flow cytometry, Real-time PCR and Western blot. Results: Our study demonstrated that Gal-3 was expressed in hypoxic pulmonary vascular adventitia and intima. The increased Gal-3 expression was responsible for hypoxic vessel remodeling and PAH development in vivo. Gal-3 was found to inhibit cell proliferation and apoptosis in cultured endothelial cells. Meanwhile endothelial cell morphology was altered and exhibited smooth muscle-like cell features as demonstrated by the expression of α-SMA after Gal-3 treatment. Gal-3 activated Jagged1/Notch1 pathways and induced MyoD and SRF. When MyoD or SRF were silenced with siRNAs, Gal-3-initiated transdifferentiation in endothelial cells was blocked as indicated by a lack of α-SMA. Conclusion: These results suggest that Gal-3 induces PAECs to acquire an α-SMA phenotype via a transdifferentiation process which depends on the activation of Jagged1/Notch1 pathways that mediate MyoD and SRF expression.

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Section: Discussionmentioning

confidence: 99%

Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

Zhang

Zeng

et al. 2018

Cell Physiol Biochem

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“…Galectin 3 is found in the nucleus, in the cytoplasm, and within extracellular spaces on cells (19,20,22,(37)(38)(39). Galectin 3 functions as an extracellular protein are well documented but it lacks a classical signal sequence that would direct the protein to ER/Golgi complex for subsequent secretion (19,39).…”

Section: Galectin 3 Localizationmentioning

confidence: 99%

“…The movement of Galectin 3 between the cytoplasm and nucleus has been an intense area of interest for many years as shuttling of Galectin 3 from the nucleus to the cytoplasm has been shown to be required to protect certain cells from stress challenge (37,38). The N terminal region containing the serine 6 phosphorylation site has been implicated in nuclear transport as mutation of serine 6 prevents export of Galectin 3 to the cytoplasm (37,38).…”

Section: Galectin 3 Localizationmentioning

confidence: 99%

“…The N terminal region containing the serine 6 phosphorylation site has been implicated in nuclear transport as mutation of serine 6 prevents export of Galectin 3 to the cytoplasm (37,38). While the CRD is critical for carbohydrate binding, this structural domain is also crucial for Galectin 3 localization.…”

Section: Galectin 3 Localizationmentioning

confidence: 99%

“…Galectin 3 has emerged as an important nuclear protein and both nuclear import sequences (nuclear localization sequence; NLS) and nuclear export sequences (NES) can be found within the CRD (37,38,45). Monomeric Galectin 3 is imported to the nucleus by passive diffusion while multimeric Galectin 3 is moved into the nucleus via an Importin-mediated mechanism A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 8 46).…”

Section: Galectin 3 Localizationmentioning

confidence: 99%

See 2 more Smart Citations

Galectin 3 as a guardian of the tumor microenvironment

Ruvolo

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

178

165

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Galectin 3 is a member of a family of β-galactoside binding proteins and has emerged as an important regulator of diverse functions critical in cancer biology including apoptosis, metastasis, immune surveillance, molecular trafficking, mRNA splicing, gene expression, and inflammation. Galectin 3's ability to support cancer cell survival by intra-cellular and extra-cellular mechanisms suggests this molecule is an important component of the tumor microenvironment that potentially could be targeted for therapy. Data is emerging that Galectin 3 is elevated in many cancers including solid tumors and the cancers of the blood. Galectin 3 also appears to be a key molecule produced by tumor microenvironment support cells including mesenchymal stromal cells (MSC) to suppress immune surveillance by killing T cells and interfering with NK cell function and by supporting metastasis. Levels of Galectin 3 increase in the MSC of aging mice and perhaps this contributes to the development of cancer in the elderly. Galectin 3 modulates surface protein expression of a diverse set of glycoproteins including CD44 by regulating endocytosis of these proteins. In addition, Galectin 3 binding to receptor kinases such as CD45 and the T cell receptor is critical in the regulation of their function. In this review I will examine the various mechanisms how Galectin 3 supports chemoresistance and metastasis in solid tumors and in leukemia and lymphoma. I will also discuss possible therapeutic strategies to target this Galectin for cancer therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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Unraveling the pathophysiologic role of galectin‐3 in chronically injured liver

Ezhilarasan

2023

Journal Cellular Physiology

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Galectin‐3 (Gal‐3) previously referred to as S‐type lectins, is a soluble protein that specifically binds to β‐galactoside carbohydrates with high specificity. Gal‐3 plays a pivotal role in a variety of pathophysiological processes such as cell proliferation, inflammation, differentiation, angiogenesis, transformation and apoptosis, pre‐mRNA splicing, metabolic syndromes, fibrosis, and host defense. The role of Gal‐3 has also been implicated in liver diseases. Gal‐3 is activated upon a hepatotoxic insult to the liver and its level has been shown to be upregulated in fatty liver diseases, inflammation, nonalcoholic steatohepatitis, fibrosis, cholangitis, cirrhosis, and hepatocellular carcinoma (HCC). Gal‐3 directly interacts with the NOD‐like receptor family, pyrin domain containing 3, and activates the inflammasome in macrophages of the liver. In the chronically injured liver, Gal‐3 secreted by injured hepatocytes and immune cells, activates hepatic stellate cells (HSCs) in a paracrine fashion to acquire a myofibroblast like collagen‐producing phenotype. Activated HSCs in the fibrotic liver secrete Gal‐3 which acts via autocrine signaling to exacerbate extracellular matrix synthesis and fibrogenesis. In the stromal microenvironment, Gal‐3 activates cancer cell proliferation, migration, invasiveness, and metastasis. Clinically, increased serum levels and Gal‐3 expression were observed in the liver tissue of nonalcoholic steatohepatitis, fibrotic/cirrhotic, and HCC patients. The pathological role of Gal‐3 has been experimentally and clinically reported in the progression of chronic liver disease. Therefore, this review discusses the pathological role of Gal‐3 in the progression of chronic liver diseases.

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Nuclear transport of galectin-3 and its therapeutic implications

Cited by 69 publications

References 149 publications

Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

Galectin-3- Mediated Transdifferentiation of Pulmonary Artery Endothelial Cells Contributes to Hypoxic Pulmonary Vascular Remodeling

Galectin 3 as a guardian of the tumor microenvironment

Unraveling the pathophysiologic role of galectin‐3 in chronically injured liver

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