Par-4 as a therapeutic target in cancer and other diseases

The tumor suppressor Par-4 is a multi-faceted protein with intracellular cytoplasmic and nuclear functions, as well as extracellular paracrine functions. Intracellular Par-4 acts by interacting, via its Par-4 amino-terminal fragment (PAF) domain, centrally placed selective for apoptosis in cancer (SAC) domain, or carboxyl-terminal leucine zipper (LZ) domain, with other proteins to regulate downstream gene transcription or posttranslational events. These activities are integral to developmental processes in specific tissues, inhibition of cellular transformation, tumor growth and metastasis and Par-4 implements them by apoptosis-dependent or -independent mechanisms. Extracellular Par-4 functions via its cell surface GRP78 (csGRP78) receptor that allows Par-4 to trigger signaling pathways to endoplasmic reticulum (ER) stress induction and apoptosis. Moreover, both intracellular and extracellular Par-4 regulate inflammation and EMT that are associated with cancer, metastasis, and a broad range of morbidities. A number of strategies are being tested to reinstate the Par-4 regulated pathways in order to overcome diseases associated with loss of Par-4 such as cancer or schizophrenia and depression, or to impede the active involvement of Par-4 in Alzheimer's, Parkinson's, cardiac aging, diabetes, and other diseases in which Par-4 acts, in consort with other incriminating pathways, to sensitize the cells to apoptosis. This chapter addresses some of the strategies that utilize the key biochemical features of Par-4 such as transcription regulation by its LZ domain, binding or sequestration of functionally significant proteins by its LZ or PAF domain, or receptor mediated signaling by its SAC domain for effectively targeting various diseases. Moreover, as Par-4 loss is associated with therapy resistance and tumor relapse, secreted or intracellular Par-4 levels may guide prognosis and treatment decisions.