RN1, a novel galectin-3 inhibitor, inhibits pancreatic cancer cell growth in vitro and in vivo via blocking galectin-3 associated signaling pathways

Abstract

Galectin-3 (Gal-3) has been implicated in pancreatic ductal adenocarcinoma (PDAC), and its candidacy as a therapeutic target has been evaluated. Gal-3 is widely upregulated in tumors, and its expression is associated with the development and malignancy of PDAC. In the present study, we demonstrate that a polysaccharide, RN1, purified from the flower of Panax notoginseng binds to Gal-3 and suppresses its expression. In addition, RN1 markedly inhibits PDAC cells growth in vitro, in vivo and in patient-derived xenografts. Mechanistically, RN1 binds to epidermal growth factor receptor (EGFR) and Gal-3, thereby disrupting the interaction between Gal-3 and EGFR and downregulating extracellular-related kinase (ERK) phosphorylation and the transcription factor of Gal-3, Runx1 expression. Inhibiting the expression of Runx1 by RN1, suppresses Gal-3 expression and inactivates Gal-3-associated signaling pathways, including the EGFR/ERK/Runx1, BMP/smad/Id-3 and integrin/FAK/JNK signaling pathways. In addition, RN1 can also bind to bone morphogenetic protein receptors (BMPR1A and BMPR2) and block the interaction between Gal-3 and the BMPRs. Thus, our results suggest that a novel Gal-3 inhibitor RN1 may be a potential candidate for human PDAC treatment via multiple targets and multiple signaling pathways.

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits pancreatic cancer cell proliferation and induces apoptosis via the EGFR pathway and caspase signaling

“…PA has been shown to induce apoptosis through the caspase pathway [25]. However, heat-inactivated PA does not have the capacity to induce apoptosis [26–27]. Consistent with previous reports, we found that inactivated PA did not induce apoptosis in pancreatic cancer cells.…”

Galectin‐3 modulates postnatal subventricular zone gliogenesis

“…Since BMP signaling in the SVZ reduces oligodendrogenesis, and promotes astrocyte differentiation (Gomes et al, ) we examined the potential role of this signaling pathway in Gal‐3 function. We first confirmed that Gal‐3 binds to BMPR1α as has been suggested (Zhang et al, ) and then tested the hypothesis that BMPR1α is necessary for Gal‐3's effects. We expressed Gal‐3, Flag‐tagged BMPR1α, and HA‐tagged BMPR2 in HEK293T cells and determined if Gal‐3 and BMPR1α and/or BMPR2 co‐immunoprecipitate.…”

“…We propose that the mechanism whereby Gal‐3 increases BMP signaling and regulates gliogenic fate choices involves direct interaction between Gal‐3 and BMPR1α. There was evidence that BMPR1α and BMPR2 are glycosylated and bind Gal‐3 in other systems (Hirschhorn, Levi‐Hofman, Danziger, Smorodinsky, & Ehrlich, ; Zhang et al, ). Interestingly, loss of BMPR1α glycosylation reduced its expression on the cell membrane and decreased Smad1/5/8 phosphorylation (Hirschhorn et al, ).…”

“…The downstream effect of increased pSmad1/5/8 is a hallmark of BMP signaling. Gal‐3 can bind to a variety of glycosylated receptors such as the EGFR and transforming growth factor beta (TGFBR) receptors, delaying their endocytosis and prolonging their activation (Partridge et al, ; Zhang et al, ). We postulate that a similar mechanism may prolong and enhance BMPR1α signaling, but further studies are needed to validate that idea.…”

Galectin‐3 exacerbates ox‐LDL‐mediated endothelial injury by inducing inflammation via integrin β1‐RhoA‐JNK signaling activation

“…activates RhoA, thus upregulating JNK signaling, an important branch of the MAPK (mitogen-activated protein kinase), which plays an important role in many physiological and pathological processes,such as cell stress, inflammation and apoptosis (Wang et al, 2016;L. Zhang et al, 2017).…”