Dear Editor,

Carcinogenesis often involves defects in apoptosis that are mediated by endogenous inhibitors of cell death, including Bcl-2, IAPs, and FLIP.1, 2 ARC (Apoptosis Repressor with a CARD (caspase recruitment domain)) is an endogenous inhibitor of apoptosis that is expressed primarily in terminally differentiated cells such as cardiac and skeletal myocytes and neurons.3, 4 In contrast to most apoptosis inhibitors, which interfere with circumscribed portions of either the extrinsic (death receptor) or intrinsic (mitochondrial/ER) death pathways, ARC antagonizes both central death cascades.4, 5 We have recently demonstrated that this inhibition is mediated by ARC’s direct binding to components of each pathway via nonhomotypic death-fold interactions.5 Thus, ARC’s binding to Fas, FADD, and procaspase-8 precludes formation of the death inducing signaling complex (DISC), disabling the extrinsic pathway. ARC’s interaction with Bax prevents Bax conformational activation and translocation to the mitochondria, antagonizing the intrinsic pathway. In this way, ARC potently inhibits a wide array of death signals. As inhibition of apoptosis has been implicated in carcinogenesis, we hypothesized that ARC is induced in cancer and plays a functionally important role.

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