| First Author | Ballista-Hernández J | Year | 2017 |
| Journal | Mol Cancer Res | Volume | 15 |
| Issue | 7 | Pages | 831-841 |
| PubMed ID | 28360037 | Mgi Jnum | J:243128 |
| Mgi Id | MGI:5907758 | Doi | 10.1158/1541-7786.MCR-16-0218 |
| Citation | Ballista-Hernandez J, et al. (2017) Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer. Mol Cancer Res 15(7):831-841 |
| abstractText | Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers; however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1+/-) gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer. Repair kinetics of AOM-induced mtDNA damage was evaluated using qPCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild-type (WT) and Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses, and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/- animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/- mice displayed an increased proliferative index and histologic abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM-induced colorectal cancer.Implications: AOM, a colorectal cancer carcinogen, generates damage to the mitochondrial genome, and the BER enzyme APE1 is required to maintain its integrity. Mol Cancer Res; 15(7); 831-41. (c)2017 AACR. |
