This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rossi, A. Articles by Santoro, M. G. Search for Related Content PubMed PubMed Citation Articles by Rossi, A. Articles by Santoro, M. G.

Targeting the Heat Shock Factor 1 by RNA Interference: A Potent Tool to Enhance Hyperthermochemotherapy Efficacy in Cervical Cancer

¹ Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche; and ² Department of Biology, University of Rome Tor Vergata, Rome, Italy

Requests for reprints: M. Gabriella Santoro, Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy. Phone: 39-06-7259-4822; Fax: 39-06-7259-4821; E-mail: santoro{at}bio.uniroma2.it.

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°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. (Cancer Res 2006; 66(15): 7678-85)

This article has been cited by other articles:

				S. Sami, N. Hoti, H.-M. Xu, Z. Shen, and X. Huang Valproic Acid Inhibits the Growth of Cervical Cancer both In Vitro and In Vivo J. Biochem., September 1, 2008; 144(3): 357 - 362. [Abstract] [Full Text] [PDF]

				R. Valgardsdottir, I. Chiodi, M. Giordano, A. Rossi, S. Bazzini, C. Ghigna, S. Riva, and G. Biamonti Transcription of Satellite III non-coding RNAs is a general stress response in human cells Nucleic Acids Res., February 2, 2008; 36(2): 423 - 434. [Abstract] [Full Text] [PDF]