Discovery and Overview of Par-4

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that was first identified as an immediate early gene in a differential screen for genes induced during the process of apoptosis in prostate cancer cells. Par-4 is ubiquitously expressed in normal human and rodent cells and tissues but is downregulated, mutated, or inactivated in most cancer cells. Functionally, elevated levels of Par-4 induce apoptosis in cancer cells and experimental tumors or sensitize normal and cancer cells to the apoptotic action of diverse insults. Par-4 contains several functional domains, including a leucine zipper domain at the carboxy terminus, selective for apoptosis of cancer cells (SAC) domain naturally placed in the center of the molecule, and Par-4 amino-terminal fragment, which regulate its tumor suppressor and pro-apoptosis function. Par-4 is a unique tumor suppressor protein expressed both intracellularly in the cytoplasm and nucleus and extracellularly. Protein kinase A activates intracellular Par-4 by phosphorylation at Thr155 residue in rat Par-4 or Thr163 in human Par-4. Activated intracellular Par-4 induces the Fas (CD95)/FasL apoptotic pathway and also inhibits NF-κB cell survival pathway. On the other hand, Akt1 inactivates Par-4 by phosphorylation at S249 in rat Par-4 or S228 in human Par-4. Extracellular Par-4 acts via cell surface receptor glucose-regulated protein 78 (GRP78) to induce caspase-8/caspase-3 and apoptosis. Whether intracellular or extracellular, Par-4 induces cancer-selective apoptosis without harming normal cells, making Par-4 an attractive target in cancer therapy. Moreover, Par-4 plays key roles in epithelial mesenchymal transition, inflammation, neuronal degenera-tion, diabetes, and cardiac and retinal apoptosis. In recent years, FDA-approved drugs and new compounds that can stimulate secretion of Par-4 from normal cells of the body to induce paracrine apoptosis of cancer cells have been identified, and clinical trials are ongoing. Thus, Par-4 research has progressed from the bench to the bedside to impact the longevity of cancer patients. This chapter provides a succinct description of research on the discovery of Par-4, leading to its key domains, interactive partners, and regulation along with mechanistic evidence supporting Par-4 function.