Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3

Abstract

Galectin-3, a multifunctional lectin, is involved during cancer progression. Previous observations showed that both cytosolic expression and nuclear exclusion of galectin-3 in human prostate cancer cells were associated to progression of the disease. In this study, we examined the biological roles of galectin-3 when expressed either in the nucleus or in the cytosol. LNCaP, a galectin-3-negative human prostate cancer cell line, was used to generate transfectants expressing galectin-3 either in the nucleus or in the cytosol. No changes in cell morphology, proliferation, attachment to laminin-1 or androgen dependency were observed. Cytoplasmic galectin-3 induced significantly increased Matrigel invasion, anchorage-independent growth and in vivo tumor growth and angiogenesis, and decreased inducible apoptosis. Surprisingly, nuclear galectin-3 affected these parameters in an opposite fashion with an overall antitumoral activity. Thus, our study demonstrates that galectin-3 exerts opposite biological activities according to its cellular localization: nuclear galectin-3 plays antitumor functions and cytoplasmic galectin-3 promotes tumor progression.

Involvement of decreased Galectin‐3 expression in the pathogenesis and progression of prostate cancer

“…Interestingly, when Gal-3 protein was still detectable within the malignant areas, there was a shift from a nuclear towards an intra-cytoplasmatic expression. Following validation of the latter observation in a CaP-derived cell line, nuclear or cytoplasmic Gal-3 expression was concluded to reveal an anti-tumor function or to promote tumor progression, respectively [5]. In this context, Ellerhorst et al [16] further evaluated the tumorsuppressive function of Gal-3 in cell lines transfected with a Gal-3 vector.…”

“…As shown before for parameters of the PKB/Akt pathway [19], the histologically still benign tissue shows molecular characteristics that are very similar to those detectable in the primary solid malignant lesions. Therefore, Gal-3 protein might be an additional and valuable molecular tool not only to augment the diagnosis of malignant intra-prostatic disease but to also determine the biological activity with regard to the intra-cellular localization of the protein [5]. The observation that already benign glands in the neighborhood of the primary solid tumors as well as PIN lesions tissues exhibit a staining pattern that is substantially different from that in prostate specimens obtained from patients with benign prostatic disease might help to differentiate more precisely between benign and malignant biopsies as supposed for small needle biopsies from thyroid cancer [20][21][22].…”

“…Whereas Irimura et al [4] described Gal-3 expression to be negatively correlated to the metastatic behavior of human colorectal carcinomas [5], this observation could not be confirmed by Lotz et al who, however, demonstrated Gal-3 to be down-regulated in cancerous when compared with non-malignant tissue samples [6].…”

Importin-mediated Nuclear Translocation of Galectin-3

“…The nuclear localization of Gal-3 is probably associated with normal cell proliferation because it is a required factor in the splicing of pre-mRNA (10). In cancer, Gal-3 plays a significant role in tumor progression (11)(12)(13)(14)(15)(16). It exerts a growth-promoting effect and cell cycle regulation through induction of cyclin D1 and c-Myc in the nuclei of human breast epithelial cells (11)(12)(13).…”

“…In the nuclei of papillary thyroid cancer cells, Gal-3 interacts with the thyroid-specific TTF-1 and up-regulates its transcriptional activity, contributing to proliferation (15). In prostate cancer cells, nuclear Gal-3 suppressed malignancy whereas cytoplasmic Gal-3 promoted tumorigenicity through a mechanism yet to be determined (16). In vivo, the cytoplasmic versus nuclear expression of Gal-3 is associated with tumor invasion and metastasis (17)(18)(19)(20)(21)(22).…”