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

Abstract

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 MPG or XRCC1 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 MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

“…Moreover, in context of intrinsic BER imbalance, PARP inhibition could paradoxically impair temozolomide-induced cytotoxicity [72]. Consensual upregulation of key genes involved in BER is observed only in a minority of cases of CRC patients [73]. In conclusion, further studies should address clinical-stage assays for evaluating BER status and therefore potentially predicting the expected benefit from the use of BER inhibitors as sensitizers to the DNA damage induced by temozolomide.…”

The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer

“…The fact that defects in various components of NER and MMR have been shown to contribute to certain cancers indicates that the mutations that arise from inhibition of these repair mechanisms are certainly an important causative factor to cancer. For this reason, although BER has not been studied as thoroughly as NER and MMR in the context of cancer, it may have a significant role in the perpetuation of bacterial infection and inflammation mediated cancers such as gastric cancer and, to some degree, colorectal cancer (Wallace et al, 2012 ; Leguisamo et al, 2017 ). Various human DNA glycosylases have already been implicated in various types of cancer.…”

Proteomic Analysis of Protein Ubiquitination Events in Human Primary and Metastatic Colon Adenocarcinoma Tissues

“…Loss of p53 not only induce tumor initiation and progression but also allows tumors to more quickly gain a full repertoire of metastatic facilitators (31). Modulation of base excision repair can alter cell metabolism and response to DNA damage and thereby overcome 5-FU chemotherapeutic resistance in colorectal cancer (32). Deregulation of the cyclin-dependent kinase subunits (CDKs) in cell cycle always leads to an uncontrolled proliferation of cancer cells and hence cell cycle is a crucial therapeutic target for anti-cancer treatment (33).…”