Induction of the apoptosis inhibitor ARC in cancer
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Apoptosis is critical in the biology of metazoans during development, tissue homeostasis, and clearance of transformed cells. Conversely, dysregulation of apoptosis contributes to the pathogenesis of multiple diseases including cancer. Cancer cells frequently escape cell death by overexpressing endogenous inhibitors of apoptosis. ARC, Apoptosis Repressor with CARD (caspase recruitment domain), is an endogenous inhibitor of apoptosis that is expressed primarily in terminally differentiated cells such as myocytes and neurons. ARC is unique among apoptosis inhibitors in that it potently antagonizes both the intrinsic and extrinsic death pathways through multiple mechanisms, some of which our lab has delineated. We have also discovered that ARC is induced in a variety of primary human epithelial cancers (breast, colon, ovary, and cervix) and renders breast cancer cells resistant to killing by radio- and chemo-therapy. Currently the mechanisms that mediate ARC induction during cancer are not known. We first screened cancer cell lines and noted that levels of N-Ras and ARC track together in several human breast and colon cancer cell lines, suggesting that Ras may be a regulator of ARC abundance. Next, we altered levels/activity of Ras in normal and cancer cell lines and assessed changes in ARC levels. Overexpression of constitutively active Ras mutants increases the abundance of ARC protein. Conversely, knockdown of endogenous N-Ras in cancer cells decreases ARC protein levels. In the Ras knockdown cells, RNA analysis revealed a 30% decrease in ARC transcription and pulse chase analysis demonstrated a 40% decrease in ARC protein half life. ARC transcription is mediated, in part, by the MAP kinase signaling pathway. ARC degradation is mediated by both the proteasome and lysosomal pathways. Analysis of MMTV-HaRas transgenic mice demonstrated the induction of ARC protein by oncogenic Ras in the mammary epithelium in vivo. This study supports a model in which Ras induces high levels of ARC protein by increasing ARC transcription and decreasing ARC degradation.