Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Biol Ther. 2009 Oct;8(19):1815-25. doi: 10.4161/cbt.8.19.9435.
Melanoma in its advanced stages is resistant not only to chemotherapy but also to radiation treatment. In line with efforts to identify genes that are key regulators of the disease and as such, may prove valuable targets for adjuvant and neo-adjuvant therapy of melanomas, we previously reported the presence of Serial Analysis of Gene Expression (SAGE) tags, corresponding to the Ataxia Telangiectasia Mutated (ATM) gene, in SAGE libraries generated from tissues representing primary and metastatic melanomas. In the present study, we document that ATM is expressed at high levels in advanced-stage melanomas. Given its crucial role in the cellular response to DNA double-strand breaks (DSB), ionizing radiation, and UV damage, we pursued a series of functional studies involving the targeting of ATM by way of RNA interference or an ATM-specific small-molecule inhibitor, followed by exposure of the cells to ionizing radiation or radiation combined with a DNA-intercalating drug, to test the hypothesis that the high-level expression of ATM prevents melanoma cells from undergoing apoptosis in response to DNA DSB-inducing treatments. However, unlike as demonstrated in the case of other malignancies, our findings summarized herein do not point to ATM as a pivotal DNA damage sensor for advanced-stage melanomas, raising the possibility that in these cells, genes other than ATM regulate and control the repair of DNA DSB.
晚期黑色素瘤不仅对化疗而且对放射治疗具有抗性。为了鉴定出疾病的关键调节基因，这些基因可能成为黑色素瘤辅助和新辅助治疗的有价值的靶点，我们之前曾报道过在来自原发性和转移性黑色素瘤组织的 SAGE 文库中存在 Serial Analysis of Gene Expression (SAGE) 标签，对应于 Ataxia Telangiectasia Mutated (ATM) 基因。在本研究中，我们证明 ATM 在晚期黑色素瘤中高表达。鉴于其在细胞对 DNA 双链断裂 (DSB)、电离辐射和 UV 损伤的反应中的关键作用，我们进行了一系列功能研究，包括通过 RNA 干扰或 ATM 特异性小分子抑制剂靶向 ATM，然后使细胞暴露于电离辐射或与 DNA 嵌入药物联合使用，以验证高表达的 ATM 是否可防止黑色素瘤细胞对诱导 DNA DSB 的治疗产生凋亡的假设。然而，与其他恶性肿瘤的情况不同，我们在此总结的发现并未将 ATM 作为晚期黑色素瘤的关键 DNA 损伤传感器，这表明在这些细胞中，除了 ATM 之外的其他基因调控和控制 DNA DSB 的修复。
