Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development.
The unfolded protein response (UPR) is an evolutionarily conserved mechanism that activates both proapoptotic and survival pathways to allow eukaryotic cells to adapt to endoplasmic reticulum (ER) stress. Although the UPR has been implicated in tumorigenesis, its precise role in endogenous cancer remains unclear. A major UPR protective response is the induction of the ER chaperone GRP78/BiP, which is expressed at high levels in a variety of tumors and confers drug resistance in both proliferating and dormant cancer cells. To determine the physiologic role of GRP78 in in situ-generated tumor and the consequence of its suppression on normal organs, we used a genetic model of breast cancer in the Grp78 heterozygous mice where GRP78 expression level was reduced by about half, mimicking anti-GRP78 agents that achieve partial suppression of GRP78 expression. Here, we report that Grp78 heterozygosity has no effect on organ development or antibody production but prolongs the latency period and significantly impedes tumor growth. Our results reveal three major mechanisms mediated by GRP78 for cancer progression: enhancement of tumor cell proliferation, protection against apoptosis, and promotion of tumor angiogenesis. Importantly, although partial reduction of GRP78 in the Grp78 heterozygous mice substantially reduces the tumor microvessel density, it has no effect on vasculature of normal organs. Our findings establish that a key UPR target GRP78 is preferably required for pathophysiologic conditions, such as tumor proliferation, survival, and angiogenesis, underscoring its potential value as a novel therapeutic target for dual antitumor and antiangiogenesis activity.
Dong
Dezheng
D
Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, California 90089-9176, USA.
Ni
Min
M
Li
Jianze
J
Xiong
Shigang
S
Ye
Wei
W
Virrey
Jenilyn J
JJ
Mao
Changhui
C
Ye
Risheng
R
Wang
Miao
M
Pen
Ligaya
L
Dubeau
Louis
L
Groshen
Susan
S
Hofman
Florence M
FM
Lee
Amy S
AS
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006579:Heterozygote; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D051742:Transcription Factor CHOP / Q000235:genetics; D019076:Transgenes / Q000502:physiology; D047368:Tumor Burden / Q000235:genetics
C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D051742:Transcription Factor CHOP; D020169:Caspases