Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy

• Published in: Oncotarget Vol. 8; no. 33; pp. 54199 - 54214
• Main Authors: Leguisamo, Natalia M, Gloria, Helena C, Kalil, Antonio N, Martins, Talita V, Azambuja, Daniel B, Meira, Lisiane B, Saffi, Jenifer
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 15.08.2017
• Subjects: Research Paper; temozolomide; base excision repair; colorectal cancer; prognosis; energy metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.14909

Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients' clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing or were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low , and expression. Imbalancing BER by overexpression of , but not , sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.