Tyrosine-phosphorylated Galectin-3 Protein Is Resistant to Prostate-specific Antigen (PSA) Cleavage

Balan, Vitaly; Nangia‐Makker, Pratima; Kho, Dhong Hyo; Wang, Yi; Raz, Avraham

doi:10.1074/jbc.c111.331686

Cited by 41 publications

(40 citation statements)

References 44 publications

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“…LnCaP transfectants secreting full-length (1–250 aa) and cleaved (33–250 aa, 63–250 aa) Gal-3 were generated using Lipofectamine® LTX and Plus™ transfection reagent (Invitrogen) and p3xFLAG-MYC-CMV-25 expression vector (Sigma-Aldrich) containing a preprotrypsin leader sequence for secretion following previous study (1, 12). Recombinant Gal-3-V5 was created using the pET30as (modified pET30a) vector containing Gal-3 sequence as described (1, 13). …”

Section: Methodsmentioning

confidence: 99%

“…Structurally, human Gal-3 is a β-galactoside-binding protein comprising 250 amino acid residues and is a chimeric gene-product composed of three distinct structural domains: a short NH 2 -terminal domain containing a phosphorylation site, a repeated collagen α-like sequence and a C-terminal domain containing a single carbohydrate recognition domain (CRD) composed of 140 amino acids (10). Due to its unique molecular structure, Gal-3 was reported to be a substrate for enzymatic cleavage by MMPs and prostate specific antigen PSA at Gly 32 -Ala 33 , Ala 62 -Tyr 63 , and Tyr 107 -Gly 108 (11–13). This proteolytic modification of secretory factors is named the degradome-peptidome (14).…”

Section: Introductionmentioning

confidence: 99%

“…In humans, more than 500 proteases such as MMPs and PSA and their substrates, including Gal-3, are categorized in this manner (15), any of which could significantly affect the TME. Past studies showed that the cleaved forms of extracellular Gal-3 by breast and prostate carcinomas modulates angiogenesis and cell migration (12, 13) and is associated with malignancy in primary lesions (11, 16). However, the cleavage status of Gal-3 in metastatic lesions remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

et al. 2016

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Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone tumor microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including TRAP, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and co-localized with myosin-2A along the surface of cell-cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

et al. 2016

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“…124 c-Abl/Arg also play a role in motility/invasion of prostate cancer cells, as c-Abl/Arg-mediated phosphorylation of the carbohydrate-binding protein, galectin-3, prevented galectin-3 cleavage by PSA, increasing full-length extracellular galectin-3, which promoted wound healing and Matrigel invasion. 125,126 Thus, there is accumulating evidence that activation of c-Abl/Arg promotes prostate cancer progression.…”

Section: Prostate Cancermentioning

confidence: 99%

“…One possibility may involve staining tumor serial sections with antibodies directed against (1) c-Abl and Arg to examine overall expression, (2) c-Abl/Arg substrates (e.g., Crk/CrkL, cortactin, WAVE3, galectin-3) 83,100,101,103,123,125,126 to indirectly examine kinase activity, and (3) proteins known to act downstream of c-Abl/Arg in a particular cancer type (e.g., STAT3, p38, p68, ERK5). 83,86,89,127 Alternatively, for tumor types containing low levels of stromal tissue and other non-tumor-associated cells, direct assessment of activity could be determined by kinase assay on tumor homogenates if enough sample is available.…”

Section: Clinical Targeting Of Abl Family Kinases In Solid Tumorsmentioning

confidence: 99%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

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Galectin-3 Promotes ROS, Inflammation, and Vascular Fibrosis in Pulmonary Arterial Hypertension

Barman

Bordán

Bátori

et al. 2021

Advances in Experimental Medicine and Biology

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Tyrosine-phosphorylated Galectin-3 Protein Is Resistant to Prostate-specific Antigen (PSA) Cleavage

Cited by 41 publications

References 44 publications

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

Galectin-3 Cleavage Alters Bone Remodeling: Different Outcomes in Breast and Prostate Cancer Skeletal Metastasis

Activation of Abl Family Kinases in Solid Tumors

Galectin-3 Promotes ROS, Inflammation, and Vascular Fibrosis in Pulmonary Arterial Hypertension

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