Systemic Par-4 inhibits non-autochthonous tumor growth

Abstract

The tumor suppressor protein Par-4 (prostate apoptosis response-4) is spontaneously secreted by normal and cancer cells. Extracellular Par-4 induces caspase-dependent apoptosis in cancer cell cultures by binding, via its effector SA C domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SA C has not been validated in animal models. We show that Par-4/SA C-transgenic mice express systemic Par-4/SA C protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SA C pro-apoptotic activity can be transferred from these cancer-resistant transgenic mice to cancer-susceptible mice by bone marrow transplantation. Moreover, intravenous injection of recombinant Par-4 or SA C protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SA C is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy. © 2011 Landes Bioscience.