1,721,088 research outputs found
The emerging role of FKBP51 in melanoma: characterization of a promising molecular target for innovative therapies
No full textMelanoma is a malignant skin cancer with high metastatic potential. The
number of melanoma cases worldwide is increasing faster than any other cancer. The prognosis is bad in the advanced stages of the disease due to resistance to conventional anti-cancer treatments. Patients diagnosed with advanced stage melanoma continue to pose a significant challenge for clinicians. Although many therapeutic regimens for metastatic melanoma have been tested, very few achieve response rates greater than 25%. There is much hope for targeted therapies and promising agents include those that act on apoptosis-regulating molecules. Very recently, we have identified that an immunophilin, namely FK506 binding protein (FKBP) 51 controls response of melanoma to DNA damaging agents, such as anthracyclines compounds. The aim of this study was to investigate the possible role of FKBP51 in the control of response to ionizing radiation (IR) in malignant melanoma. FKBP51-silenced cells showed reduced clonogenic potential after irradiation compared with non-silenced cells. After IR, we observed apoptosis in FKBP51-silenced cells and autophagy in non-silenced cells. FKBP51 was required for the activation of Rx-induced NF-kappaB, which in turn inhibited apoptosis by
stimulating X-linked inhibitor of apoptosis protein and promoting authophagymediated Bax degradation. Using a tumor-xenograft mouse model, the in vivo pretreatment of tumors with FKBP51-siRNA provoked massive apoptosis after irradiation. Immunohistochemical analysis of 10 normal skin samples and 80 malignant cutaneous melanomas showed that FKBP51 is a marker of melanocyte malignancy, correlating with vertical growth phase and lesion thickness. Moreover, we provided evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. Finally, we expanded the study to other types of cancer, including ovarian, pancreatic, prostate, colon, breast and lung cancer and found a strong correlation between the protein expression and malignity of the tumoral lesions. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma and a potential novel tumoral biomarker
Un biomarcatore tumorale (in particolare di melanoma) predittivo di risposta alla immunoterapia
No full textElevator pitch per la presentazione di un biomarcatore da noi brevettato ad aziende potenzialmente interessate al suo sviluppo e/o al finanziamento del nostro progetto
FKBP12 controls tumor response to TGF-β induced apoptosis
No full textLoss of response to transforming growth factor-beta (TGF-β) is thought to contribute to the progression of chronic lymphocytic leukemia. FKBP12-knockout mouse show an over-activation of the TGF-β signal; our findings demonstrate that most chronic lymphocytic leukemia cells escape the homeostatic control of TGF-β and that FK506, the canonical ligand of FKBP, can activate the TGF-β signal and restores the signal in a proportion of non-responsive samples. We particularly demonstrate that FK506 activates the TGF-β receptor I kinase activity, which transduces apoptosis by a mitochondrial-dependent pathway
FKBP51 isoforms in cancer
No full textPresentation on the FK506 binding protein (FKBP) 51 as central molecular player in melanoma progression, because of its role in the positively regulation of cancer stemness, epithelial to mesenchimal transition genetic program and NF-κB-induced chemo and radio-resistance. Moreover, the talk was also focused on preliminary data showing that the spliced isoform of FKBP51, FKBP51s, is an immune signature of melanoma patients, virtually associated with tumor-induced immune tolerance and able to monitoring melanoma patient subjected to immune-therapy
Programmed death ligand 1 (PD-L1) sustains glioblastoma stemness and tumorigenic potential
No full textGliomas aberrantly express programmed cell death ligand-1 (PD-L1), which has a pivotal role in immunoevasion. The splicing isoform of FKBP5, termed FKBP51s, is a PD-L1 foldase, assisting the immune checkpoint molecule in maturation and expression on the plasma membrane. The concept that PD-L1 supports tumor-intrinsic properties is increasingly emerging. Our findings confirm the pro-tumoral effect of PD-L1 on human glioma cell survival, stemness capacity and resistance, and show how, by targeting FKBP51s PD-L1 and its pro-tumoral properties could be hampered, thereby affecting the self-renewal and growth capacities of glioblastoma cells in vitro and in vivo
Investigating immune modulatory aspects of melanoma to gain novel molecular tools for advancing in cancer immunotherapies
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FKBP51 orchestrates the evil axis EMT/cancer stemness/drug resistance in malignant melanoma. A matter of protein/protein interaction
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