RICERCA ITALIANA     

I FATTORI DA STRESS HSF E NF-kB COME BERSAGLI STRATEGICI PER TERAPIE ANTITUMORALI INNOVATIVE

Università degli Studi di Roma "Tor Vergata"

Abstract

Constitutive activation of cell survival signaling pathways is a general mechanism underlying tumor development and resistance to therapy, and constitutes a major clinical problem in cancer. Two of these pathways, the HSF and IKK/NF-kB pathway, have been recently shown to be of primary importance in the development of cancer resistance to chemotherapy and radiation-therapy. Moreover, the IKK/NF-kB pathway has been shown to be constitutively activated in several types of aggressive cancers, and this event has been associated with resistance to apoptosis induced by chemotherapeutic drugs. Based on these observations, NF-kB inhibitors targeted to the proteasome have been recently introduced in the therapy for multiple myeloma and other chemo-resistant types of malignancies. The initial results obtained with this novel approach to chemotherapy encourage the search for novel, more specific NF-kB inhibitors, especially targeted to the IKK kinase.
Cyclopentenone prostanoids (cyPG), a class of arachidonic acid metabolites characterized by the presence of an alpha,beta-unsaturated carbonyl group in the cyclopentane ring, are emerging as potent anti-neoplastic agents in a multiplicity of in vitro and in vivo cancer models, including breast, prostate, colon, lung, gastric, skin and lymphoid tumors. In most types of cancer, cyPG inhibit tumor cell proliferation and induce apoptosis; however, the mechanism of cyPG anti-neoplastic activity has not been elucidated as yet. The Italian>>>

Coordinatore Scientifico del Programma di Ricerca

Maria Gabriella SANTORO, Universita' degli Studi di ROMA ""Tor Vergata""

Obiettivo del Finanziamento

The nuclear transcription factor NF-kB normally exists as an inactive cytoplasmic complex, whose predominant form is a heterodimer composed of p50 and p65 (Rel A) subunits, bound to inhibitory proteins of the IkB family, and is activated in response to a variety of pathogenic stimuli, including viral and bacterial infection, and exposure to inflammatory cytokines (Santoro, 2003; see reference list in the Results section). In most instances, induction requires the activation of the IkB kinase IKK via stimulation of different signal transduction pathways involving distinct scaffolding and signaling proteins (Karin and Lin, 2002). IKK is a multisubunit complex, containing two catalytic subunits (IKK-a and IKK-b), which are able to form homo- or heterodimers, and the IKK-g regulatory subunit. The IKK signalosome complex phosphorylates IkBs triggering their ubiquitination and proteasome-mediated degradation. Release of IkBs results in nuclear translocation of NF-kB and its binding to DNA at specific kB-sites, rapidly inducing a variety of genes encoding, among others, cell adhesion molecules, inflammatory and chemotactic cytokines, cytokine receptors and enzymes that produce inflammatory mediators, including COX-2 and iNOS (Santoro, 2003). As a consequence, NF-kB is considered a critical regulator of the inflammatory and the innate immune responses (Karin and Lin, 2002). However, more recently, NF-kB activation has been connected with multiple aspects of oncogenesis, including>>>

Durata

36 mesi