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A Novel Role for p73 in the Regulation of Akt-Foxo1a-Bim Signaling and Apoptosis Induced by the Plant Lectin, Concanavalin A

Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Munna L. Agarwal, Department of Genetics, Case Western Reserve University, Cleveland, OH 44106. Phone: 216-368-5674; Fax: 216-368-8919; E-mail: munnaagarwal{at}hotmail.com.

Virtually all human cancers encounter disruption of the "p53 network." From a therapeutic point of view, it is important to devise strategies that eliminate cancer cells, which are often defective in functional p53 and protect p53-expressing normal cells. By comparing the response of a pair of isogenic cell lines, we identify a plant-derived compound, Concanavalin A (Con A), which differentially kills p53-null cells. Further, we find that p53 family member, p73, plays a critical role that is unmasked in the absence of p53. Con A treatment leads to induction of p73 and several others that are important mediators of apoptosis and act downstream, such as p21, Bax, Foxo1a, and Bim. Inactivation of p73 reverses the expression of these proteins and apoptosis. Inhibition of Akt activation sensitizes otherwise resistant cells. These observations thus reveal a novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis especially when p53 is absent. [Cancer Res 2007;67(12):5617–21]

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