Dataset Information

FKBP51 increases the tumour-promoter potential of TGF-beta.

ABSTRACT:

Background

FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). In recent years, research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF-? in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect between FKBP51 and TGF-? in melanoma progression.

Methods

SAN and A375 melanoma cell lines were utilized for this study. Balb/c IL2? NOD SCID served to assess the ability to colonize organs and metastasize of different cell lines, which was evaluated by in vivo imaging. Realtime PCR and western blot served for measurement of mRNA and protein expression, respectively.

Results

By comparing the metastatic potential of two melanoma cell lines, namely A375 and SAN, we confirmed that an increased capability to colonize murine organs was associated with increased levels of FKBP51. A375 melanoma cell line expressed FKBP51 mRNA levels 30-fold higher in comparison to the SAN mRNA level and appeared more aggressive than SAN melanoma cell line in an experimental metastasis model. In addition, A375 expressed, more abundantly than SAN, the TGF-? and the pro angiogenic TGF-? receptor type III (T?RIII) factors. FKBP51 silencing produced a reduction of TGF-? and T?RIII gene expression in A375 cell line, in accordance with previous studies. We found that the inducing effect of TGF-? on Sparc and Vimentin expression was impaired in condition of FKBP51 depletion, suggesting that FKBP51 is an important cofactor in the TGF-? signal. Such a hypothesis was supported by co immunoprecipitation assays, showing that FKBP51 interacted with either Smad2,3 and p300. In normal melanocytes, FKBP51 potentiated the effect of TGF-? on N-cadherin expression and conferred a mesenchymal-like morphology to such round-shaped cells.

Conclusions

Overall, our findings show that FKBP51 enhances some pro oncogenic functions of TGF-?, suggesting that FKBP51-overexpression may help melanoma to take advantage of the tumor promoting activities of the cytokine.

SUBMITTER: Romano S

PROVIDER: S-EPMC3906759 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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FKBP51 increases the tumour-promoter potential of TGF-beta.

Romano Simona S D'Angelillo Anna A D'Arrigo Paolo P Staibano Stefania S Greco Adelaide A Brunetti Arturo A Scalvenzi Massimiliano M Bisogni Rita R Scala Iris I Romano Maria Fiammetta MF

Clinical and translational medicine 20140127 1

<h4>Background</h4>FKBP51 (FKBP5 Official Symbol) is a large molecular weight component of the family of FK506 binding proteins (FKBP). In recent years, research studies from our laboratory highlighted functions for FKBP51 in the control of apoptosis and melanoma progression. FKBP51 expression correlated with the invasiveness and aggressiveness of melanoma. Since a role for TGF-β in the enhanced tumorigenic potential of melanoma cells is widely described, we hypothesized a cooperative effect bet ...[more]

PMID: 24460977

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Project description:Despite advances in treatment for metastatic melanoma patients, patients with liver metastasis have an unfavorable prognosis. A better understanding of the development of liver metastasis is needed. The multifunctional cytokine Transforming Growth Factor β (TGF-β) plays various roles in melanoma tumors and metastasis, affecting both tumor cells and cells from the surrounding tumor microenvironment. To study the role of TGF-β in melanoma liver metastasis, we created a model to activate or repress the TGF-β receptor pathway in vitro and in vivo in an inducible manner. For this, we engineered B16F10 melanoma cells to have inducible ectopic expression of a constitutively active (ca) or kinase-inactive (ki) TGF-β receptor I, also termed activin receptor-like kinase (ALK5). In vitro, stimulation with TGF-β signaling and ectopic caALK5 expression reduced B16F10 cell proliferation and migration. Contrasting results were found in vivo; sustained caALK5 expression in B16F10 cells in vivo increased the metastatic outgrowth in liver. Blocking microenvironmental TGF-β did not affect metastatic liver outgrowth of both control and caALK5 expressing B16F10 cells. Upon characterizing the tumor microenvironment of control and caALk5 expressing B16F10 tumors, we observed reduced (cytotoxic) T cell presence and infiltration, as well as an increase in bone marrow-derived macrophages in caALK5 expressing B16F10 tumors. This suggests that caALK5 expression in B16F10 cells induces changes in the tumor microenvironment. A comparison of newly synthesized secreted proteins upon caALK5 expression by B16F10 cells revealed increased secretion of matrix remodeling proteins. Our results show that TGF-β receptor activation in B16F10 melanoma cells can increase metastatic outgrowth in liver in vivo, possibly through remodeling of the tumor microenvironment leading to altered infiltration of immune cells. These results provide insights in the role of TGF-β signaling in B16F10 liver metastasis and could have implications regarding the use of TGF-β inhibitors for the treatment of melanoma patients with liver metastasis.

Dataset Information

FKBP51 increases the tumour-promoter potential of TGF-beta.

Background

Methods

Results

Conclusions

Publications

FKBP51 increases the tumour-promoter potential of TGF-beta.

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