title: Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer.
abstract: 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) andApex1+/-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 andApex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT andApex1+/-animals, whereas a significant increase in nuclear DNA lesions was detected in tumors fromApex1+/-mice. Finally, tumors fromApex1+/-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. ©2017 AACR.
authors.affiliation: Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Joan
authors.initials: J
authors.lastname: Ballista-Hernández
authors.affiliation: Department of Pharmaceutical Sciences, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Margaly
authors.initials: M
authors.lastname: Martínez-Ferrer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Roman
authors.initials: R
authors.lastname: Vélez
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Climent
authors.affiliation: Department of Pharmaceutical Sciences, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Sánchez-Vázquez
authors.affiliation: Department of Biochemistry, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Ceidy
authors.initials: C
authors.lastname: Torres
authors.affiliation: Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Adlin
authors.initials: A
authors.lastname: Rodríguez-Muñoz
authors.affiliation: Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
authors.forename: Sylvette
authors.initials: S
authors.lastname: Ayala-Peña
authors.affiliation: Department of Physiology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico. carlos.torres27@upr.edu.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Ramos
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000187:drug effects*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D004195:Disease Models, Animal; D054629:Genome, Mitochondrial; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D002273:Carcinogens; D004272:DNA, Mitochondrial; C486216:Apex1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D001397:Azoxymethane