The inhibitors of apoptosis (IAPs) and their emerging role in cancer

The inhibitor of apoptosis protein family has been characterized over the p ast 5 years, initially in baculovirus and more recently in metazoans, The I APs are a widely expressed gene family of apoptotic inhibitors from both ph ylogenic and physiologic points of view. The diversity of triggers against which the IAPs suppress apoptosis is greater than that observed for any oth er family of apoptotic inhibitors including the bcl-2 family. The central m echanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of an d by the transcription factor NF-kappa B, Although evidence for a direct on cogenic role for the IAPs has yet to be delineated, a number of lines of ev idence point towards this class of protein playing a role in oncogenesis, T he strongest evidence for IAP involvement in cancer is seen in the IAP call ed survivin, Although not observed in adult differentiated tissue, survivin is present in most transformed cell lines and cancers tested to date. Surv ivin has been shown to inhibit caspase directly and apoptosis in general, m oreover survivin protein levels correlate inversely with 5 year survival ra tes in colorectal cancer. Recent data has also implicated survivin in cell cycle control, The second line of evidence for IAP involvement in cancer co mes from their emerging role as mediators and regulators of the anti-apopto tic activity of v-Rel and NF-kappa B transcription factor families. The IAP s have been shown to be induced by NF-kappa B or v-Rel in multiple cell lin es and conversely, HIAP1 and HIAP2 have been shown to activate NF-kappa B p ossibly forming a positive feed-back loop, Overall a picture consistent wit h an IAP role in tumour progression rather than tumour initiation is emergi ng making the IAPs an attractive therapeutic target.