TY - JOUR
T1 - Suppressive roles of calreticulin in prostate cancer growth and metastasis
AU - Alur, Mahesh
AU - Nguyen, Minh M.
AU - Eggener, Scott E.
AU - Jiang, Feng
AU - Dadras, Soheil S.
AU - Stern, Jeffrey
AU - Kimm, Simon
AU - Roehl, Kim
AU - Kozlowski, James
AU - Pins, Michael
AU - Michalak, Marek
AU - Dhir, Rajiv
AU - Wang, Zhou
N1 - Funding Information:
Supported by grants from the National Institute of Health, R01 DK51193, Prostate Cancer Specialized Program Of Research Excellence (SPORE), CA90386, Department of Defense Prostate Cancer Research Program, DAMD17-01-1-0088. M.A. and F.J. were supported by Chicago Baseball Charity Pre-doctoral Fellowship. S.E.E. was funded by a Ruth L. Kirschstein National Research Service Award from the National Institute of Health Training Grant.
PY - 2009/8
Y1 - 2009/8
N2 - Calreticulin is an essential, multifunctional Ca2+-binding protein that participates in the regulation of intracellular Ca2+ homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.
AB - Calreticulin is an essential, multifunctional Ca2+-binding protein that participates in the regulation of intracellular Ca2+ homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.
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U2 - 10.2353/ajpath.2009.080417
DO - 10.2353/ajpath.2009.080417
M3 - Article
C2 - 19608864
AN - SCOPUS:68449088415
SN - 0002-9440
VL - 175
SP - 882
EP - 890
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -
