ABSTRACT
Title
NEMO-binding domain peptide induces apoptosis of human melanoma cells lines by inhibiting NF-κB activation.
Authors
E. Panza1, M. Tersigni1, G. Belardo2, M. Napolitano3, P. A. Ascierto4, G. Cirino1, A. Ialenti1 and A. Ianaro1
1Dept. of Experimental Pharmacology, University of Naples Federico II, Naples; 2Dept. of Biology, University of Rome Tor Vergata, Roma; 3Oncologic Immunology, National Tumour Institute, Fondazione Pascale, Naples, Italy;4Medical Oncology and Innovative Therapy National Tumor Institute, Fondazione Pascale, Naples, Italy.
1Dept. of Experimental Pharmacology, University of Naples Federico II, Naples; 2Dept. of Biology, University of Rome Tor Vergata, Roma; 3Oncologic Immunology, National Tumour Institute, Fondazione Pascale, Naples, Italy;4Medical Oncology and Innovative Therapy National Tumor Institute, Fondazione Pascale, Naples, Italy.
Abstract
Melanoma is the most aggressive form of skin cancer and its incidence has increased in the last decade. One important target identified in melanoma tumor progression is the Nuclear Factor-κB (NF-κB) pathway. In vitro studies have shown that IKK is constitutively active in human melanoma cells as compared to normal melanocytes, leading to NF-κB activation which in turn regulates the expression of anti-apoptotic proteins. These events are implicated as major molecular mechanisms for melanocytes transformation (Ueda Y. and Richmond, 2006). It has been found that a short cell-permeable peptide spanning the IKKβ NEMO binding domain (NBD), disrupted the association of NEMO with IKKs in vitro and blocked TNFα-induced NF-κB activation in vivo (May et al., 2000). In the present study we investigated the effect of the NBD peptide on survival of several human melanoma cell lines (A375, WM115, SK-Mel-5) as well as on the IKK/NF-κB signalling pathway. We report that NBD peptide inhibits the proliferation of all human melanoma cell lines used. Inhibition of cell growth was associated with direct inhibition of i) constitutive IKK activity; ii) NF-κB DNA-binding activation; iii) induction of apoptosis in all cell lines tested. Using the A375 melanoma cell line, we show that inhibition of IKK/NF-κB signalling pathway by NBD peptide leads to down-regulation of the expression of several NF-κB-dependent antiapoptotic gene products and to the activation of caspase-3. Our studies suggest that a selective inhibition of IKK/NF-κB activation can be an effective strategy to be developed in the fight against cancer.
[1] Ueda Y. and Richmond A. 2006. Pigment Cell Res. 19: 112-124.
[2] May M., Gao X., Cao Z., Rothe M. and Goeddel D.V. 2000. Science 289:1550-1554
[1] Ueda Y. and Richmond A. 2006. Pigment Cell Res. 19: 112-124.
[2] May M., Gao X., Cao Z., Rothe M. and Goeddel D.V. 2000. Science 289:1550-1554