HSF1 activation and the control of apoptosis in chemoresistant cancers

HSF1 ACTIVATION AND THE CONTROL OF APOPTOSIS IN CHEMORESISTANT CANCERS G. Belardo, A. Rossi, S. Ciafre', A. Ciucci, P. Gianferretti, S. Roberts and M.G. Santoro Department of Biology, University of Rome Tor Vergata and Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy; Department of Chemistry, University of Manchester, Manchester, UK. Activation of the heat shock response (HSR) via HSF1 contributes to preserve cellular function and homeostasis under stress conditions, and to establish a cytoprotective state in several human diseases. In cancer, however, HSR activation has been associated with both anti- and proapoptotic responses. Heat-induced expression of cytoprotective and antiapoptotic heat shock proteins (HSP) is a known complication of hyperthermia, resulting in cancer cell thermotolerance and chemoresistance. In some instances, however, HSF1 activation may result in apoptosis induction. We have developed a library of novel potent inducers of HSF1 which are characterized by pro-apoptotic activity in several types of chemoresistant cancers. We have previously shown that HSF1 induction prevents TNF?- and mitogen-induced activation of NF-?B, a nuclear factor playing an important role in promoting inflammation, as well as cell proliferation and survival. NF-?B has been found to be constitutively activated in several types of chemoresistant cancers where it suppresses cell death pathways by switching on genes that dampen pro-apoptotic signals. We now show that activation of HSF1 by diverse chemical inducers, as well as by hyperthermia itself, results in inhibition of constitutive NF-?B activity and rapid down-regulation of the expression of NF-?B-dependent survival genes, triggering apoptosis in aggressive cancers presenting aberrant NF-?B regulation. The results suggest that the block of anti-apoptotic signaling pathways utilizing the I?B kinase IKK may play an important role in modulating HSR pro-apoptotic effects in chemoresistant cancers