Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

Abstract

Calreticulin is an essential, multifunctional Ca 2؉ -binding protein that participates in the regulation of intracellular Ca 2؉ 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.

Calreticulin is a novel independent prognostic factor for oral squamous cell carcinoma

“…However, it was also reported that CALR might inhibit growth and/or metastasis of prostate cancer cells in vitro and in vivo (11). Also, cell surface CALR has been considered as an 'eat-me' signal, and cell surface CALR might promote phagocytic uptake of cancer cells by immune systems (18,19).…”

“…Elevated expressions of CALR in the sera of patients with autoimmune diseases were also reported (12). Again, differential expression of CALR was reported in some cancer types, and in some cases CALR low-expression was found to promote cancer growth (11,12). In lung cancer, the expression level of CALR on tumor cell membrane was apparently related with the pathological grade of the tumor (12).…”

“…CALR is a 46 kDa protein which acts as a molecular chaperone and a major Ca (2+)-binding (storage) protein in the endoplasmic reticulum (ER) that ensures proper folding of glycoproteins (9)(10)(11). CALR controls a number of diverse biological processes in ER and other parts of the cell; such as gene expression, transcriptional activities, cell proliferation, phagocytosis, apoptosis and immune response (9,10).…”

“…It can also affect cell adhesion, wound healing and migration (9,10). Although there are many studies on the role of CALR in a variety cellular processes and functions, its role on human carcinogenesis still remains unclear (11).…”

“…There have been studies on the alteration of CALR expression in lung cancer, ovarian cancer, gibloblastoma, gastrointentinal cancer, breast cancer, urinary tract cancer, which indicates its role in promoting or suppressing various types of cancers (9)(10)(11). Overespression of CALR has been associated with a number of malignancies together with several types of cancers (12)(13)(14)(15).…”