6-sialyllactose ameliorates dihydrotestosterone-induced benign prostatic hyperplasia through suppressing VEGF-mediated angiogenesis

Abstract

Benign prostatic hyperplasia (BPH), a common disease in elderly males, is accompanied by non-malignant growth of prostate tissues, subsequently causing hypoxia and angiogenesis. Although VEGF-related angiogenesis is one of the therapeutic targets of prostate cancer, there is no previous study targeting angiogenesis for treatment of BPH. Dihydrotestosterone (DHT)-induced expressions of vascular endothelial growth factor (VEGF) in prostate epithelial RWPE-1 cells and human umbilical vascular endothelial cells (HUVECs). Conditioned media (CM) from DHT-treated RWPE-1 cells were transferred to HUVECs. Then, 6SL inhibited proliferation, VEGFR-2 activation, and tube formation of HUVECs transferred with CM from DHT-treated RWPE-1 cells. In the rat BPH model, 6SL reduced prostate weight, size, and thickness of the prostate tissue. Formation of vessels in prostatic tissues were also reduced with 6SL treatment. We found that 6SL has an ameliorative effect on in vitro and in vivo the BPH model via inhibition of VEGFR-2 activation and subsequent angiogenesis. These results suggest that 6SL might be a candidate for development of novel BPH drugs.

Anti-Angiogenic Property of Free Human Oligosaccharides

“…In this regard, our group recently revealed the specific components of anti-angiogenic acidic HMOs and their underlying mechanisms. Unlike other HMOs summarized in Table 1 , we identified that 3′- and 6′-sialyllactose inhibited angiogenesis ( Figure 4 ) [ 108 , 109 ]. However, their analogs, 3′-sialyl- N -lactosamine and 6′-sialyl- N -lactosamine, were unable to bind to VEGFR-2 or suppress their activation, despite the only difference being a single glycan unit, glucose, and N -acetylglucosamine [ 108 ].…”

“…Following VEGFR-2 inhibition by sialylated oligosaccharides, the downstream signaling molecules, including ERK, Akt and p-38, were also suppressed ( Figure 5 ) [ 108 , 110 ]. Furthermore, administration of sialylated oligosaccharides sufficiently inhibited angiogenesis in allograft cancer, benign prostate hyperplasia, and premature retinopathy models [ 108 , 109 , 110 ].…”

MLL5, a histone modifying enzyme, regulates androgen receptor activity in prostate cancer cells by recruiting co-regulators, HCF1 and SET1

“…These results showed that MLL5 is required for the growth of prostate cancer cells and may act synergistically with enzalutamide on apoptosis process. The function of AR in prostate cancer cell migration is also well known (25,26). When we measured the levels of epithelial and mesenchymal protein markers in DHT-treated control cell extract, the epithelial marker E-cadherin level was decreased and those of mesenchymal markers N-cadherin and vimentin increased.…”

Pharmacological Effects and Potential Clinical Usefulness of Polyphenols in Benign Prostatic Hyperplasia

“…In short, EGCG reduced the prostatic expression of VEGF, basic fibroblast growth factor (bFGF), and EGF; decreased the expression of TGF-β1, TGF-β1 receptor 1, and hypoxia-inducible factor-1α (HIF-1α); decreased the phosphorylation-Smad3 (known as mothers against decapentaplegic homolog 3); reduced the expression of AR and ER-α, enhanced ER-β expression; and enhanced miR-133a/b in BPH rats [ 107 ]. In previous reports, angiogenesis and EMT were reported to play important roles in the etiology and development of BPH [ 108 , 109 , 110 , 111 ]. Unfortunately, there is little information on the pathological roles of miR-133a/b in BPH.…”