Romano, Simona (2010) The emerging role of FKBP51 in melanoma: characterization of a promising molecular target for innovative therapies. [Tesi di dottorato] (Unpublished)

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Item Type: Tesi di dottorato
Language: English
Title: The emerging role of FKBP51 in melanoma: characterization of a promising molecular target for innovative therapies
Creators:
CreatorsEmail
Romano, Simonaromanos@dbbm.unina.it
Date: 29 November 2010
Number of Pages: 159
Institution: Università degli Studi di Napoli Federico II
Department: Biologia e patologia cellullare e molecolare "L. Califano"
Doctoral School: Medicina molecolare
PHD name: Oncologia ed endocrinologia molecolare
PHD cycle: 23
PHD Coordinator:
nameemail
Santoro, MassimoUNSPECIFIED
Tutor:
nameemail
Romano, Maria Fiammettaromano@dbbm.unina.it
Date: 29 November 2010
Number of Pages: 159
Uncontrolled Keywords: FKBP51; Melanoma; Biomarker
MIUR S.S.D.: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Area 05 - Scienze biologiche > BIO/10 - Biochimica
Additional Information: Il lavoro è stato svolto presso il Dipartimento di Biochimica e Biotecnologie Mediche (DBBM) dell'Università Federico II di Napoli
Date Deposited: 13 Dec 2010 14:48
Last Modified: 30 Apr 2014 19:44
URI: http://www.fedoa.unina.it/id/eprint/8115

Abstract

Melanoma 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.

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