Systemic Par-4 Inhibits Non-Autochthonous Tumor Growth
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 SAC domain, to cell surface GRP78 receptor. However, the functional significance of extracellular Par-4/SAC has not been validated in animal models. We show that Par-4/SAC-transgenic mice express systemic Par-4/SAC protein and are resistant to the growth of non-autochthonous tumors. Consistently, secretory Par-4/SAC 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 SAC protein inhibits metastasis of cancer cells. Collectively, our findings indicate that extracellular Par-4/SAC is systemically functional in inhibition of tumor growth and metastasis progression, and may merit investigation as a therapy.
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This study was supported by KLCR grant, NIH/ NCI grants CA060872, CA105453 and CA116658 (to V.M.R.).
Zhao, Yanming; Burikhanov, Ravshan; Brandon, Jason; Qiu, Shirley; Shelton, Brent J.; Spear, Brett T.; Bondada, Subbarao; Bryson, Scott; and Rangnekar, Vivek M., "Systemic Par-4 Inhibits Non-Autochthonous Tumor Growth" (2011). Radiation Medicine Faculty Publications. 14.