The role of GRP78 in the regulation of apoptosis and prostate cancer progression

Restricted until 17 Apr. 2010.Glucose-regulated protein 78 (GRP78), a molecular chaperone at the endoplasmic reticulum (ER), is a master regulator of ER stress and an important survival factor for cell. GRP78 protein level is highly elevated in malignant tumors and correlates with severe pathological grade and poor prognosis. It has been well established that GRP78 can affect apoptosis by regulating ER Ca2+ signaling and unfolded protein response pathway, but whether other mechanism exists remains unknown. Searching for novel partners that interact with GRP78 at the ER, we discovered that BIK, an apoptotic BH-3-only protein located principally at ER, selectively forms a complex with GRP78. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For the MCF-7/BUS breast cancer cells that require BIK to mediate estrogen starvation-induced apoptosis, overexpression of GRP78 inhibits estrogen-starvation induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by siRNA sensitizes MCF-7/BUS cells to estrogen-starvation induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. In addition to in vitro investigations, an in vivo study in a Pten conditional knockout mouse model of prostate cancer reveals that homozygous deletion of Grp78 blocks prostate cancer formation and progression initiated by Pten nullification. Our results provide multiple lines of evidence that GRP78 is a critical player in the regulation of apoptosis and the formation and progression of cancer. These results further support the concept that GRP78 represents a novel marker for cancer progression and chemo-responsiveness, as well as a novel target for cancer therapy