O6-methylguanine-DNA methyltransferase in the defense against N-nitroso compounds and colorectal cancer

Abstract

Colorectal cancer (CRC) is among the leading causes of cancer death worldwide, involving multiple dietary and non-dietary risk factors. A growing body of evidence suggests that N-nitroso compounds (NOC) play a pivotal role in the etiology of CRC. NOC are present in food and are also formed endogenously in the large intestine. Upon metabolic activation and also spontaneously, they form electrophilic species that methylate the DNA, producing N-methylated purines and O(6)-methylguanine, the latter of which bears high mutagenic and carcinogenic potential. Methylated DNA bases are removed by base excision repair initiated by the alkyladenine-DNA glycosylase, the family of AlkB homologs proteins, and the suicide enzyme O(6)-methylguanine-DNA methyltransferase (MGMT), which is the main focus of this review. We present animal models with a deficiency of MGMT that display a tremendously enhanced sensitivity toward alkylation-induced colorectal carcinogenesis, highlighting its role in the protection against the cytotoxic and mutagenic effects of alkylating agents. In line with these studies, MGMT was linked to the formation of human sporadic CRC. Colorectal tumors and precursor lesions frequently display epigenetic inactivation of MGMT resulting from promoter hypermethylation, which is tightly associated with the occurrence of G:C to A:T transition mutations in the KRAS oncogene. We also discuss clinical data, which identified the MGMT status of CRC patients as promising parameter for the treatment of metastasized CRC using alkylating anticancer drugs such as temozolomide.