A Mutation in the Carbohydrate Recognition Domain Drives a Phenotypic Switch in the Role of Galectin-7 in Prostate Cancer

Abstract

The observation that galectin-7 (gal-7) is specifically expressed in mammary myoepithelial (basal) cells prompted us to investigate whether this protein is expressed in the basal cells of other tissues. Given that breast and prostate cancer have remarkable underlying biological similarities and given the important roles of basal cells in prostate cancer, we examined the expression patterns and role of gal-7 in human prostate cancer. Using tissue microarray, we found that although gal-7 is readily expressed in basal cells in normal prostate tissue, it is downregulated in prostate cancer (PCa) cells. De novo expression of gal-7 in prostate cancer cells increases their sensitivity to apoptosis in response to etoposide and cisplatin. The assessment of a carbohydrate-recognition domain (CRD)-defective mutant form of gal-7 (R7S) showed that the ability of this protein to modulate apoptosis was independent of its CRD activity. This activity was also independent of its ability to translocate to the mitochondrial and nuclear compartments. However, CRD activity was necessary to inhibit the invasive behaviors of prostate cancer cells. In vivo, gal-7 overexpression in PCa cells led to a modest yet significant reduction in tumor size, while its CRD-defective mutant form significantly increased tumor growth compared to controls. Taken together, these results suggest that although de novo expression of gal-7 may be an interesting means of increasing the tumorigenic phenotypes of PCa cells, alterations in the CRD activity of this protein drive a phenotypic switch in its role in PCa cells. This CRD-independent activity represents a paradigm shift in our understanding of the functions of galectin. The R74S model will be useful to distinguish CRD-dependent and CRD-independent functions of gal-7 in cancer progression.

Mutation of the Galectin-3 Glycan Binding Domain (Lgals3-R200S) Enhances Cortical Bone Expansion in Male and Trabecular Bone Mass in Female Mice

“…While we did not verify that our mutant lost glycan binding function, mutation of this arginine to a serine in human galectin-3 (R186S) has been shown to prevent galectin-3 secretion and glycan binding [30,31,37]. Because mutation of the functionally equivalent arginine in galectin-7 also prevents glycan binding [32,33], we believe that the R200S mutation in galectin-3 should also be functionally equivalent. Future experiments will need to address whether this mutation in mouse galectin-3 is functionally equivalent to human galectin-3, as well as whether this mutation disrupts known intracellular interactions of galectin-3.…”

“…Mutation of a highly conserved arginine to a serine in the glycan binding domain of human galectin-3 (R186S) blocks its glycan binding and secretion [30]. While this mutant has thus far only been characterized for its lack of function extracellularly [30,31], mutation of the structurally equivalent arginine in galectin-7 blocks glycan binding, but still allows galectin-7 to function intracellularly [32,33]. It is also possible to dissociate galectin-1 glycan binding from intracellular interactions and regulation of mRNA splicing [34].…”

A New Approach to Inhibit Prototypic Galectins

“…This has been well documented for intracellular galectin activities. For example, GAL-7 interacts with intracellular BCL-2 family members via a GBS-independent interaction (26,27). Similarly, intracellular GAL-3 and -4 directly bind to beta-catenin, a non-glycosylated protein (28,29).…”

“…Our recent findings in prostate cancer showing that alterations in the GBS of GAL-7 shift the balance towards GBS-independent binding partners and drive a phenotypic switch in cancer cells emphasize the importance of GBS-independent galectin activity in cancer (40). Apart from GAL-3, which mediates protein-protein interactions via its long polypeptide tail, we know very little about how prototypic and/or tandem-repeat galectins mediate GBS-independent interactions.…”

Galectin‑7 is elevated in endometrioid (type I) endometrial cancer and promotes cell migration

“…Galectin-7 is a negative prognostic marker for ovarian cancer (17) and renal clear-cell carcinoma (18). Conversely, galectin-7 may exhibit anti-tumor properties in other types of cancer; for example, it is absent in prostate cancer cells (19), reduced in gastric cancer (20) and causes prostate and DLD-1 colon cancer cells to have greater sensitivity to apoptosis (19,21).…”