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.

To begin to test this hypothesis, lysates from 48 cancer cell lines from the NCI-60 panel were screened for ARC expression by immunoblot (not shown). ARC was present in cancer cell lines derived from breast (eg MCF-7), lung (nonsmall-cell, eg A-549), colon (eg HT-29), prostate (eg PC-3), kidney (eg A-498), and others. ARC levels were highly variable, however, even among different cell lines derived from the same tissue. For example, in contrast to HT-29 and PC-3 cells, SW-60 colon cancer cells and DU-145 prostate cancer cells exhibited low ARC levels. Within breast cancer lines, ARC was expressed at high levels in MCF-7 and T-47D cells, at intermediate levels in BT-549 and ADR-RES cells, and to a much lesser extent, in Hs578T, MDA-MB-231, MDAMB-435, and HCC1419 cells. Significant ARC was present in both estrogen receptor positive (eg MCF-7) and negative (eg BT-549) cell lines. Notably, MCF-10A and MCF-12A, immortalized epithelial cell lines derived from benign breast tissue, exhibited very low ARC levels. These data demonstrate that ARC is expressed at high levels in some, but not all, cancer cell lines.