Alpha<sub>2</sub> macroglobulin, a PSA binding protein, is expressed in human prostate stroma

Lin, Victor K.; Wang, Shih-Ya; Boetticher, Nicholas C.; Vazquez, Dolores V.; Saboorian, Hossein; McConnell, John D.; Roehrborn, Claus G.

doi:10.1002/pros.20183

Cited by 17 publications

(14 citation statements)

References 32 publications

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“…The concentration of ␣ 2 M in the serum ranges from 1 to 5 M (10). It is produced by many tissues, including prostate stroma (9). Patients with prostate cancers often demonstrate ␣ 2 M levels at the lower end of this range, presumably reflecting proteinase-dependent turnover, not a change in synthetic rate (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

“…There is, however, little other evidence indicating a direct role for PSA in disease progression. ␣ 2 M is synthesized by many tissues, particularly the liver; however, it is also produced locally in prostate stromal tissue, where it is available to complex with PSA (9). When a proteinase attacks the so-called "bait region," thiol esters in each of the four ␣ 2 M subunits rupture, and the protein undergoes a very large conformational change, exposing receptor recognition sites in each subunit (10).…”

Section: Prostate-specific Antigen (Psa)mentioning

confidence: 99%

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Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Misra

Payne

Pizzo

2011

Journal of Biological Chemistry

113

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GRP78, a well characterized chaperone in the endoplasmic reticulum, is critical to the unfolded protein response. More recently, it has been identified on the cell surface, where it has many roles. On cancer cells, it functions as a signaling receptor coupled to proproliferative/antiapoptotic and promigratory mechanisms. In the current study, we demonstrate that ligation of prostate cancer cell surface GRP78 by its natural ligand, activated ␣ 2 -macroglobulin (␣ 2 M*), results in a 2-3-fold upregulation in the synthesis of prostate-specific antigen (PSA). The PSA is secreted into the medium as an active proteinase, where it binds to native ␣ 2 M. The resultant ␣ 2 M⅐PSA complexes bind to GRP78, causing a 1.5-2-fold increase in the activation of MEK1/2, ERK1/2, S6K, and Akt, which is coupled with a 2-3-fold increase in DNA and protein synthesis. PSA is a marker for the progression of prostate cancer, but its mechanistic role in the disease is unclear. The present studies suggest that PSA may be involved in a signal transduction-dependent feedback loop, whereby it promotes a more aggressive behavior by human prostate cancer cells.Prostate-specific antigen (PSA) 2 is a serine proteinase that complexes with serum proteinase inhibitors, including ␣ 2 -macroglobulin (␣ 2 M) (1). Monitoring of PSA is generally recommended in men over 50 years old to screen for prostate cancer; however, there is significant controversy with respect to its use as a marker for the appearance of the disease (1-6). By contrast, substantial data support its use in monitoring progression and metastasis (1, 2, 5). Recently, a Phase II controlled trial suggested that immunization against PSA prolongs patient survival, suggesting a direct role for PSA in the pathobiology of the disease (7). Studies have shown that PSA produced by metastatic prostate cancer cells is involved in bone remodeling, a common feature in the bony metastasis of this disease (8). There is, however, little other evidence indicating a direct role for PSA in disease progression. ␣ 2 M is synthesized by many tissues, particularly the liver; however, it is also produced locally in prostate stromal tissue, where it is available to complex with PSA (9). When a proteinase attacks the so-called "bait region," thiol esters in each of the four ␣ 2 M subunits rupture, and the protein undergoes a very large conformational change, exposing receptor recognition sites in each subunit (10). Two receptors have been identified for activated forms of ␣ 2 M (␣ 2 M*), namely the LDL receptor-related protein (LRP) and cell surface-associated GRP78 (glucose-regulated protein of M r ϳ78,000) (10, 11). In addition to proteinases, exposure of ␣ 2 M to small primary amines or ammonia, by direct attack on the thiol esters, produces ␣ 2 M* (10). Although GRP78 is primarily known as a resident endoplasmic reticulum chaperone, it appears on the cell surface of many types of malignant cells, including human prostate cancer (12-16). Here it has many functions, including serving as an ␣ 2 M* signaling re...

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Section: Discussionmentioning

confidence: 99%

Section: Prostate-specific Antigen (Psa)mentioning

confidence: 99%

Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Misra

Payne

Pizzo

2011

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

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“…However, in patients with prostate cancers, levels below 0.7 Amol/L have been reported (19)(20)(21). Prostate cancer cells may produce a 2 M (22), which should increase the pool size of this protein. Prostate cancer cells, however, also produce the proteinase prostate cancer-specific antigen (PSA) and matrix metalloproteinases (23,24), which convert a 2 M to a 2 M* (18).…”

mentioning

confidence: 99%

Prostate Cancer Cell ProliferationIn vitroIs Modulated by Antibodies against Glucose-Regulated Protein 78 Isolated from Patient Serum

et al. 2006

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Circulating autoantibodies against the glucose-regulated protein of 78 kDa (GRP78) are present at high levels in prostate cancer patients and are a biomarker of aggressive tumor behavior. We purified the anti-GRP78 IgGs and examined their effect on 1-LN, PC-3, DU145, and LnCap human prostate cancer cells. We also evaluated its effects on the breast cancer MDA-MB231 and melanoma DM413 cell lines. The anti-GRP78 antibody binds only to cells expressing GRP78 on the surface, to a site also recognized by its physiologic agonist, activated A 2 -macroglobulin (A 2 M*). This antibody is completely specific for a peptide, including the primary amino acid sequence CNVKSDKSC, which contains a tertiary structural motif mimicking an epitope in GRP78. Tertiary structual analysis suggested the linear GRP78 primary amino acid sequence LIGRTWNDPSVQQDIKFL (Leu 98 -Leu 115 ) as the putative binding site, containing the tertiary structual arrangement described above, which was confirmed experimentally. The anti-GRP78 antibodies from prostate cancer patients recognize almost exclusively this epitope. We produced animal antibodies against both these peptides, and they are able to mimic the effects of the human antibody. Our experiments also suggest this epitope as highly immunogenic, thereby explaining the specificity of the immune response against this epitope in GRP78, observed in humans. Using 1-LN cells as a model, we show that anti-GRP78 IgG purified from the sera of these patients mimics the proproliferative effects induced by A 2 M* via the common receptor, GRP78. Furthermore, increasing concentrations of human anti-GRP78 IgG show a dose-dependent protective effect on apoptosis induced by tumor necrosis factor A.

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“…More recently, it's reported that a2M is also involved in the pathogenesis of atherosclerosis (AS) (Larionov et al 2006(Larionov et al , 2007 and plays a crucial role for the immune efficiency during ageing and in age-related diseases (Mocchegiani et al 2006). It was observed that increased expression of a2M is related to the benign prostatic hyperplasia and plays an important role in regulating the benign and malignant prostatic growth (Lin et al 2005). Wager et al demonstrated that the a2M protein level in plasma of healthy subjects correlates with age (Wagner et al 1982).…”

Section: Introductionmentioning

confidence: 96%

Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence

Huang

et al. 2011

Biogerontology

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Alpha-2-macroglobulin (α2M), a protease inhibitor, is implicated in Alzheimer's disease, atherosclerosis, and other age-related diseases. The elevated level of α2M mRNA has been described in replicative senescence and it could be used as a biomarker of the aging cells. However, the mechanism responsible for the up-regulation of its expression is still unclear. This report identified a novel transcriptional regulatory element, the α2M transcription enhancement element (ATEE), within the α2M promoter. This element differentially activates α2M expression in senescent versus young fibroblasts. Electrophoretic mobility shift assays revealed abundant complexes in senescent cell nuclear extracts compared with young cell nuclear extracts. The DNase I footprint revealed the protein-binding core sequence through which the protein binds the ATEE. Mutation within ATEE selectively abolished α2M promoter activity in senescent (but not young) cells. These results indicated the ATEE, as a positive transcription regulatory element, contributes to the up-regulation of α2M during replicative senescence.

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Alpha₂ macroglobulin, a PSA binding protein, is expressed in human prostate stroma

Cited by 17 publications

References 32 publications

Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Prostate Cancer Cell ProliferationIn vitroIs Modulated by Antibodies against Glucose-Regulated Protein 78 Isolated from Patient Serum

Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence

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Alpha2 macroglobulin, a PSA binding protein, is expressed in human prostate stroma

Cited by 17 publications

References 32 publications

Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Ligation of Prostate Cancer Cell Surface GRP78 Activates a Proproliferative and Antiapoptotic Feedback Loop

Prostate Cancer Cell ProliferationIn vitroIs Modulated by Antibodies against Glucose-Regulated Protein 78 Isolated from Patient Serum

Characterization of a novel positive transcription regulatory element that differentially regulates the alpha-2-macroglobulin gene in replicative senescence

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Alpha₂ macroglobulin, a PSA binding protein, is expressed in human prostate stroma