The Intrinsic Pathway of Apoptosis and Carcinogenesis: An Update

Abstract

A conserved, intact and tightly regulated apoptotic pathway is necessary for embryonic organogenesis, maintenance of tissue homeostasis and tumour suppression in healthy organisms. This pathway is also activated in response to hypoxia, oncogenic overexpression or DNA damage and serves to eliminate cells that have experienced lethal doses of genotoxic stress. Several studies suggest that resistance to apoptosis, also known as programmed cell death, results in the survival of mutant cells which can induce tumourigenesis. Therefore, inhibition of apoptosis is considered a requirement for tumourigenesis and thus an acquired resistance to apoptosis has become a “hallmark” for cancer. The intrinsic, or mitochondrial, pathway of apoptosis is mainly controlled by the interactions between mitochondrial and cytosolic pro- and anti-apoptotic proteins of the Bcl-2 family. Thus, resistance to apoptosis can be acquired by mutations in pro- or anti-apoptotic genes of Bcl-2 family members or in the tumour suppressor gene p53 which is the DNA damage sensor in the intrinsic apoptotic signalling circuitry. Moreover, multiple epigenetic studies have illustrated the role DNA methylation plays in the aberrant apoptosis in many human cancers, and thus in the survival of tumours. Novel therapeutics that target the intrinsic pathway of apoptosis have also been the subject of considerable investigation.