Document Detail


Targeting the heat shock factor 1 by RNA interference: a potent tool to enhance hyperthermochemotherapy efficacy in cervical cancer.
MedLine Citation:
PMID:  16885369     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Carcinoma of the uterine cervix is one of the highest causes of mortality in female cancer patients worldwide, and improved treatment options for this type of malignancy are highly needed. Local hyperthermia has been successfully used in combination with systemic administration of cisplatin-based chemotherapy in phase I/II clinical studies. Heat-induced expression of cytoprotective and antiapoptotic heat shock proteins (HSP) is a known complication of hyperthermia, resulting in thermotolerance and chemoresistance and hindering the efficacy of the combination therapy. Heat shock transcription factor 1 (HSF1) is the master regulator of heat-induced HSP expression. In the present report, we used small interfering RNA (siRNA) to silence HSF1 and to examine the effect of HSF1 loss of function on the response to hyperthermia and cisplatin-based chemotherapy in HeLa cervical carcinoma. We have identified the 322-nucleotide to 340-nucleotide HSF1 sequence as an ideal target for siRNA-mediated HSF1 silencing, have created a pSUPER-HSF1 vector able to potently suppress the HSF1 gene, and have generated for the first time human cancer cell lines with stable loss of HSF1 function. We report that, although it surprisingly does not affect cancer cell sensitivity to cisplatin or elevated temperatures up to 43 degrees C when administered separately, loss of HSF1 function causes a dramatic increase in sensitivity to hyperthermochemotherapy, leading to massive (>95%) apoptosis of cancer cells. These findings indicate that disruption of HSF1-induced cytoprotection during hyperthermochemotherapy may represent a powerful strategy to selectively amplify the damage in cancer cells and identify HSF1 as a promising therapeutic target in cervical carcinoma.
Authors:
Antonio Rossi; Stefania Ciafrè; Mirna Balsamo; Pasquale Pierimarchi; M Gabriella Santoro
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  66     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-03     Completed Date:  2006-09-28     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7678-85     Citation Subset:  IM    
Affiliation:
Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects,  physiology
Cisplatin
Combined Modality Therapy
DNA-Binding Proteins / antagonists & inhibitors*,  biosynthesis,  genetics*
Female
Gene Silencing
HSP27 Heat-Shock Proteins
HSP70 Heat-Shock Proteins / biosynthesis,  genetics
HSP90 Heat-Shock Proteins / biosynthesis,  genetics
Heat-Shock Proteins / biosynthesis,  genetics
Hela Cells
Humans
Hyperthermia, Induced / methods*
Neoplasm Proteins / biosynthesis,  genetics
RNA Interference
RNA, Small Interfering / genetics
Transcription Factors / antagonists & inhibitors*,  biosynthesis,  genetics*
Transfection
Uterine Cervical Neoplasms / drug therapy,  genetics,  pathology,  therapy*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/HSP27 Heat-Shock Proteins; 0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; 0/HSPB1 protein, human; 0/Heat-Shock Proteins; 0/Neoplasm Proteins; 0/RNA, Small Interfering; 0/Transcription Factors; 0/heat shock transcription factor; 15663-27-1/Cisplatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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