Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium.
GRP78/BiP has recently emerged as a novel biomarker for aggressive prostate cancer. Here, we report that homozygous deletion of Grp78 specifically in mouse prostate epithelium suppresses prostate tumorigenesis without affecting postnatal prostate development and growth. Mouse prostates with double conditional knockout of Grp78 and Pten exhibit normal histology and cytology, in contrast to the invasive adenocarcinoma in mouse prostates with Pten inactivation. AKT activation in Pten null prostate epithelium is inhibited by Grp78 homozygous deletion, corresponding with suppression of AKT phosphorylation by GRP78 knockdown in prostate cancer cell line. Thus, inactivation of GRP78 may represent a previously undescribed approach to stop prostate cancer and potentially other cancers resulting from the loss of PTEN tumor suppression and/or activation of the oncogenic AKT.
Fu
Yong
Y
Department of Biochemistry, University of Southern California Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA.
Wey
Shiuan
S
Wang
Miao
M
Ye
Risheng
R
Liao
Chun-Peng
CP
Roy-Burman
Pradip
P
Lee
Amy S
AS
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D004848:Epithelium / Q000473:pathology / Q000502:physiology; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse