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Myc Down-Regulation Sensitizes Melanoma Cells to Radiotherapy by Inhibiting MLH1 and MSH2 Mismatch Repair Proteins

Authors' Affiliations: ¹ Associazione Fatebenefratelli per la Ricerca-Centro Ricerca S. Pietro and ² Unita di Radioterapia Oncologica S. Pietro, Fatebenefratelli Hospital, Rome, Italy;³ II Cattedra di Oncologia Medica, II Facoltà di Medicina "La Sapienza", Rome, Italy; ⁴ Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche; ⁵ Dipartimento di Farmacologia, Università di Milano; and ⁶ Istituto Neurobiologia e Medicina Molecolare, Milan, Italy

Requests for reprints: Barbara Bucci, Associazione Fatebenefratelli per la Ricerca-Centro Ricerca S. Pietro, Fatebenefratelli Hospital, Via Cassia 600, 00189 Rome, Italy. Phone: 39-633582873; Fax: 39-633251278; E-mail: bucci.barbara{at}fbfrm.it.

Purpose: Melanoma patients have a very poor prognosis with a response rate of <1% due to advanced diagnosis. This type of tumor is particularly resistant to conventional chemotherapy and radiotherapy, and the surgery remains the principal treatment for patients with localized melanoma. For this reason, there is particular interest in the melanoma biological therapy.

Experimental Design: Using two p53 mutant melanoma models stably expressing an inducible c-myc antisense RNA, we have investigated whether Myc protein down-regulation could render melanoma cells more susceptible to radiotherapy, reestablishing apoptotic p53-independent pathway. In addition to address the role of p53 in the activation of apoptosis, we studied the effect of Myc down-regulation on radiotherapy sensitivity also in a p53 wild-type melanoma cell line.

Results: Myc down-regulation is able per se to induce apoptosis in a fraction of the cell population (40% at 72 hours) and in combination with radiation efficiently enhances the death process. In fact, 80% of apoptotic cells are evident in Myc down-regulated cells exposed to radiation for 72 hours compared with 13% observed after only radiation treatment. Consistent with the enhanced apoptosis is the inhibition of the MLH1 and MSH2 mismatch repair proteins, which, preventing the correction of ionizing radiation mismatches occurring during DNA replication, renders the cells more prone to radiation-induced apoptosis.

Conclusions: Data herein reported show that Myc down-regulation lowers the apoptotic threshold in melanoma cells by inhibiting MLH1 and MSH2 proteins, thus increasing cell sensitivity to radiation in a p53-independent fashion. Our results indicate the basis for developing new antitumoral therapeutic strategy, improving the management of melanoma patients.

Key Words: melanoma • c-myc • radiotherapy • apoptosis • MMR

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