Suppressing the high-level expression and function of ATM in advanced-stage melanomas does not sensitize the cells to ionizing radiation.
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.
Moschos
Stergios J
SJ
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Dodd
Nicole R
NR
Jukic
Drazen M
DM
Fayewicz
Shelley L
SL
Wang
Xiaolei
X
Becker
Dorothea
D
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D015151:Immunoblotting; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D009367:Neoplasm Staging; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases