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Originally published online as doi:10.2353/ajpath.2009.080417 on July 16, 2009

Published online before print July 16, 2009
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(American Journal of Pathology. 2009;175:882-890.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080417

Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

Mahesh Alur*, Minh M. Nguyen*{dagger}, Scott E. Eggener*, Feng Jiang*, Soheil S. Dadras*, Jeffrey Stern*, Simon Kimm*, Kim Roehl{ddagger}, James Kozlowski*§, Michael Pins§, Marek Michalak||, Rajiv Dhir**{dagger}{dagger} and Zhou Wang*{dagger}§{ddagger}{ddagger}

From the Departments of Urology,* Pathology, and Molecular Pharmacology and Biological Chemistry,{ddagger}{ddagger} and the Robert H. Lurie Comprehensive Cancer Center,§ Feinberg School of Medicine, Northwestern University, Chicago, Illinois; the Departments of Urology,{dagger} and Pathology,** and the University of Pittsburgh Cancer Institute,{dagger}{dagger} University of Pittsburgh, Pittsburgh, Pennsylvania; the Departments of Psychiatry and Surgery/Urology,{ddagger} Washington University, St. Louis, Missouri; and the Department of Biochemistry,|| University of Alberta, Edmonton, Canada

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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