Follistatin as potential therapeutic target in prostate cancer

Sepporta, Maria Vittoria; Tumminello, Francesca Maria; Flandina, Carla; Crescimanno, Maria; Giammanco, Marco; Guardia, Maurizio La; Majo, Danila Di; Leto, Gaetano

doi:10.1007/s11523-013-0268-7

Cited by 26 publications

(19 citation statements)

References 96 publications

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“…Nevertheless, our results suggest that the observed increase in follistatin could be an independent pro-oncogenic molecule. In support of the previous suggestion, in vitro studies on prostate cancer have revealed that the progression of tumour and development of resistance to the growth inhibitory actions of activin-A were associated with higher levels of follistatin [62, 63]. Alternatively, the up-regulation of follistatin may plausibly be a compensatory mechanism against the pathological increase of activin-A since a more recent study has also reported that follistatin inhibited cancer progression in a subset of pancreatic cancer cell lines that are known to highly express both activin β-subunits [64].…”

Section: Discussionmentioning

confidence: 74%

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

Refaat

El-Shemi

et al. 2016

BMC Cancer

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BackgroundActivin-A may exert pro- or anti-tumorigenic activities depending on cellular context. However, little is known about its role, or the other mature activin proteins, in colorectal carcinoma (CRC). This study measured the expression of activin βA- & βB-subunits, activin type IIA & IIB receptors, smads 2/3/4/6/7 and follistatin in CRC induced by azoxymethane (AOM) in rats. The results were compared with controls and disseminated according to the characteristics of histopathological lesions.MethodsEighty male Wistar rats were allocated into 20 controls and the remaining were equally divided between short ‘S-AOM’ (15 weeks) and long ‘L-AOM’ (35 weeks) groups following injecting AOM for 2 weeks. Subsequent to gross and histopathological examinations and digital image analysis, the expression of all molecules was measured by immunohistochemistry and quantitative RT-PCR. Activin-A, activin-B, activin-AB and follistatin were measured by ELISA in serum and colon tissue homogenates.ResultsColonic pre-neoplastic and cancerous lesions were identified in both AOM groups and their numbers and sizes were significantly (P < 0.05) greater in the L-AOM group. All the molecules were expressed in normal colonic epithelial cells. There was a significantly (P < 0.05) greater expression of βA-subunit, IIB receptor and follistatin in both pre-neoplastic and cancerous tissues. Oppositely, a significant (P < 0.05) decrease in the remaining molecules was detected in both AOM groups. Metastatic lesions were only observed within the L-AOM group and were associated with the most significant alterations of all molecules. Significantly higher concentrations of activin-A and follistatin and lower activin-AB were also detected in both groups of AOM. Tissue and serum concentrations of activin-A and follistatin correlated positively, while tissue activin-AB inversely, and significantly with the numbers and sizes of colonic lesions.ConclusionsNormal rat colon epithelial cells are capable of synthesising, controlling as well as responding to activins in a paracrine/autocrine manner. Colonic activin systems are pathologically altered during tumorigenesis and appear to be time and lesion-dependent. Activins could also be potential sensitive markers and/or molecular targets for the diagnosis and/or treatment of CRC. Further studies are required to illustrate the clinical value of activins and their related proteins in colon cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2914-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 74%

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

Refaat

El-Shemi

et al. 2016

BMC Cancer

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“…For example, FST288 binds to heparin sulfate proteoglycans with a high affinity and may function as a local regulator by potentially preventing the autocrine, endocrine and paracrine actions of activin (39). Additionally, FST288-activin binding complex can interact with cell-surface proteoglycans followed by the internalization and subsequent degradation of this complex with lysosomal enzymes (3,5,6). Conversely, FST315 is predominantly localised in the circulation, consistent by its low binding affinity for heparin, and its binding to activin appears to be irreversible (5).…”

Section: Abstract Follistatin (Fst) As a Single-chain Glycosylated mentioning

confidence: 99%

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Shi

Resaul

Owen

et al. 2016

CGP

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Abstract. Follistatin (FST) Follistatin (FST), which was first isolated from porcine and bovine follicular fluid (1, 2), was initially described as a protein involved in the regulation of the secretion of folliclestimulating hormone. This monomeric glycosylated polypeptide chain is encoded by a single gene located on the long arm chromosome 5q11.2 (3), which through alternative splicing may be transcribed into the mRNA precursors, FST317 and FST344. From these precursors, three major FST isoforms may be produced, namely FST288 (from pre-FST317), FST315 (from pre-FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus. These three main FST isoforms can also be glycosylated to yield six further FST isoforms that were previously identified in bovine (4) and porcine (5, 6) follicular fluid. At the core, all FST isoforms contain a 63 residue N-terminal domain and three follistatin domains, termed FSD1, FSD2 and FSD3. These domains comprise 73-77 amino acid residues and are characterised by an arrangement of 10 conserved cysteine residues (7). Both FST288 and FST315 are differentially expressed in human tissues (6-9). FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (10, 11). Some molecules such as activin, transforming growth factor-beta (TGFβ), forkhead domain transcription factor L2 (12, 13), gonadotropin-releasing hormone (14), zinc finger protein (GLI2) (15), dexamethasone (16), androgens (17), activators of winglessrelated integration site (WNT) signalling (18, 19) and 1,25-dihydroxyvitamin D (20) have been shown to regulate the transcription of the FST gene. In addition, down-regulation of FST gene expression by peroxisome proliferator-activated receptor gamma (PPARγ) or the transcription factor epiprofin (21, 22) has been shown.As an antagonist of TGFβ superfamily member activin, FST seems to primarily function in relation to the role that activin plays. Along with FST, activin acts as a pleiotropic growth factor system, which is involved in proliferation, differentiation, and apoptosis of a number of cell types (23-28). As such, the functions of the FST isoforms are therefore linked to their binding affinity for activin (6,10,11,(29)(30)(31)(32)(33)(34)(35)(36)(37). In fact, this critical binding and neutralisation of activin, either partial or complete, is based on the order of at least two of the FST cysteine domains and its Nterminal (38), conferring a difference in affinities for activin between the FST isoforms. The binding complex between activin and FST generally occurs in a 1:2 ratio, where the two FST molecules, connected C-terminus to N-425

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“…The Bio-Plex system has been used to simultaneously analyze numerous kinds of biomolecules for biomarker discovery. Using this assay system, Martinetti et al investigated circulating prognostic biomarkers, such as SDF-1 carcinoma, malignant gliomas, and prostate cancer [22][23][24][25] . FST levels, which were measured by ELISA, were significantly higher in the 1273/99 cell line than in the other three cell lines (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Chen et al reported that FST is a novel biomarker for the diagnosis of lung adenocarcinoma 22) . Furthermore, Sepporta et al demonstrated that FST is a potential therapeutic target in prostate cancer 39) . Here, we report that increased FST expression is significantly associated with resistance to TKI treatment in synovial sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma

Qiao

Kito²,

Takai³

et al. 2017

J. Electrophor

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SUMMARYSarcoma is a rare malignancy with an aggressive clinical course. Tyrosine kinase inhibitors (TKIs) have emerged as effective drugs in targeted therapy for malignancies; in particular, pazopanib was recently approved for the treatment of sarcoma. However, as only a limited proportion of patients exhibit favorable response to treatment with TKIs, predictive biomarkers of response to these drugs are urgently needed. In this study, we attempted to identify predictive biomarkers for response to TKIs in synovial sarcoma. We performed a magnetic bead-based assay (Bio-Plex) using synovial sarcoma cell culture supernatant and validated the results by ELISA and western blotting. Cellular protein and mRNA expression levels of candidate biomarkers were evaluated by western blotting and RT-PCR. Gene expression profiling of candidate biomarkers was conducted by meta-analysis of publicly available gene expression data from 149 patients with synovial sarcoma. We found that follistatin (FST) was significantly highly expressed in TKI-resistant cells. Moreover, cell proliferation was decreased following gene silencing of FST. Meta-analysis revealed that the mRNA expression of FST varied among the 149 patients with synovial sarcoma, and that 23 genes were co-expressed with FST; these included genes encoding receptor tyrosine kinase-like orphan receptor 1, Sal-like protein 4, and signal transducer CD24. This study suggested that FST represents a candidate predictive biomarker for response to treatment with TKIs in synovial sarcoma. Secretomics is a promising approach for predictive biomarker exploration. The utility of FST as a predictive biomarker for response to treatment with TKIs in synovial sarcoma should be further validated using clinical samples.

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Follistatin as potential therapeutic target in prostate cancer

Cited by 26 publications

References 96 publications

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

Activins and their related proteins in colon carcinogenesis: insights from early and advanced azoxymethane rat models of colon cancer

Clinical and Therapeutic Implications of Follistatin in Solid Tumours

Secretomics identifies follistatin as a predictive biomarker for response to treatment with tyrosine kinase inhibitors in synovial sarcoma

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