Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress

• Published in: Molecular cancer research Vol. 11; no. 4; pp. 370 - 380
• Main Authors: Zimmerman, Kristin M, Jones, Rebecca M, Petermann, Eva, Jeggo, Penelope A
• Format: Journal Article
• Language: English
• Published: United States 01-04-2013
• Subjects: Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Growth Processes - physiology; DNA Damage; DNA Replication - physiology; Gene Knockdown Techniques; Humans; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - pathology; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Transfection
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-12-0491

Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumor cells express high levels of origin-licensing proteins, we examined whether depletion of such factors might specifically sensitize tumor versus nontumor cells. Consistent with previous findings, we observed that three tumor-derived cell lines overexpress ORC1, a licensing component, compared with four nontumor cell lines and that a greater level of ORC1 was required to maintain viability in the tumor cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitized the tumor-derived cells to hydroxyurea and H202 but did not affect the sensitivity of the nontumor lines. Similar results were observed following depletion of ORC6 or CDC6. Furthermore, codepletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT nontumor fibroblasts and more dramatically caused hypersensitivity to hydroxyurea. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in nontumor BJhTERT cells diminished viability. Collectively, these findings suggest that tumor cells may have a reliance on origin-licensing capacity, suggesting that licensing factors could represent a target for drug-based cancer therapy.