Systemic Interferon-α (IFN-α) Treatment Leads to Stat3 Inactivation in Melanoma Precursor Lesions

Abstract

Background: In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon a (IFN-a)-mediated growth suppression in vitro. Materials and Methods: To determine whether IFN-a, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-a. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electro-phoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-a treatment. Results: The results of the investigations provided evidence that, as a result of systemic IEN-a treatment, Statl and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated.

The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3

“…Our results may also relate to the anti-STAT3 effects of IFN-␣ observed in some clinical studies (48). STAT3 joins a group of IFN-inhibited pro-growth transcription factors, which until now comprised c-myc (49) and E2F (50), although very different mechanisms of inhibition are involved in each case.…”

Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas

“…First, Cbp/p300 acts as a cofactor for the Microphthalmia transcription factor (MITF), 28 a regulator of pigment cell development and survival, 29 which cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. 30 Second, the signal transducer and activator of transcription 3 (Stat3), expressed at high levels in both nevi and melanomas, 17 is acetylated by Cbp/p300, which, in turn, enables Stat3 to form stable dimers. 31 Unlike OPN and Cbp/p300, PERP is not present among the top 50 genes that lead the list of genes, which are downregulated in the group2 encompassing "advanced-stage" tissue samples.…”

STAT proteins: novel molecular targets for cancer drug discovery

“…Constitutive Stat3 tyrosine or serine phosphorylation has been detected in breast carcinomas (Garcia et al, 1997(Garcia et al, , 2000Watson and Miller, 1995), head and neck squamous cell carcinomas (Grandis et al, 1998(Grandis et al, , 2000aSong and Grandis, 2000), as well as lymphomas and leukemias (Catlett-Falcone et al, 1999a,b, 2000Co er et al, 2000;Frank et al, 1997;GouilleuxGruart et al, 1996;Weber-Nordt et al, 1996;Zhang et al, 1996c). Other cases of tumors with constitutive Stat3 activity include prostate, melanoma, pancreas, ovarian and brain (Cattaneo et al, 1998;Florenes et al, 1999;Kirkwood et al, 1999;Lou et al, 2000;Magrassi et al, 1999;Pansky et al, 2000;Schrell et al, 1998; L Mora, R Garcia, J Seigne, T Bowman, G Niu, J Pow-Sang, J Diaz, C Muro-Cacho, D Coppola, T Yeatman, J Cheng, S Nicosia, S Shivers, T Landowski, D Reintgen, W Dalton, H Yu and R Jove, unpublished results). These observations make it compelling to examine the role of Stat3 signaling in malignant progression to establish whether the constitutive Stat3 activation present in human tumors is essential for the malignancy.…”