Metastatic Prostate Cancer Cells Secrete Methylglyoxal-Derived MG-H1 to Reprogram Human Osteoblasts into a Dedifferentiated, Malignant-like Phenotype: A Possible Novel Player in Prostate Cancer Bone Metastases

Abstract

Bone metastases from prostate cancer (PCa) result from a complex cross-talk between PCa cells and osteoblasts (OB). Thus, targeting this interplay has become an attractive strategy to interfere with PCa bone dissemination. The agents currently used in clinical trials have proved ineffective, boosting research to identify additional mechanisms that may be involved in this two-directional talk. Here, we investigated whether and how 5-hydro-5-methylimidazolone (MG-H1), a specific methylglyoxal (MG)-derived advanced glycation end product (AGE), was a novel player in the dialogue between PCa and OB to drive PCa bone metastases. Conditioned medium from osteotropic PC3 PCa cells, pre-treated or not with a specific MG scavenger, was administrated to human primary OB and cell morphology, mesenchymal trans-differentiation, pro-osteogenic determinants, PCa-specific molecules, and migration/invasion were studied by phase-contrast microscopy, real-time PCR, western blot and specific assays, respectively. We found that PC3 cells were able to release MG-H1 that, by binding to the receptor for AGEs (RAGE) on OB, reprogrammed them into a less-differentiate phenotype, endowed with some PCa-specific molecular features and malignant properties, in a mechanism involving reactive oxidative species (ROS) production and NF-kB pathway activation. These findings provide novel insights into the mechanisms of PCa osteoblastic metastases and foster in vivo research toward new therapeutic strategies interfering with PCa/OB cross-talk.

The Glyoxalase System Is a Novel Cargo of Amniotic Fluid Stem-Cell-Derived Extracellular Vesicles

“…It is known that MG-H1 can act through the receptor for AGEs, RAGE [ 34 ]. By using an Ab specific for a region of the protein common to both full-length cell surface or soluble RAGE, we did not find RAGE expression in both HASC-P10 and HASC-P100 EVs ( Figure 4 ).…”

“…MG-H1 can signal by binding to RAGE [ 34 ]. Differently from other studies that detected the presence of RAGE on neuronal derived-exosomes [ 38 , 43 ], RAGE was not expressed in both HASC EVs, indicating that the function of these EVs, as well as the role of MG-H1, does not depend on this receptor.…”

“… Protein level of the Receptor for Advanced Glycation End Products (RAGE) in HASC-P10 and HASC-P100 EVs, evaluated by Western blot. A: Positive control (human primary osteoblasts, PromoCell (Heidelberg, Germany) [ 34 ]). …”

Ketorolac Loaded Poly(lactic-co-glycolic acid) Coating of AZ31 in the Treatment of Bone Fracture Pain

“…BSCL138 primary human fibroblasts (IZSLER, Brescia, Italy) were cultured in Eagle’s minimum essential medium (MEM, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS, Thermo Fisher Scientific, Waltham, MA, USA), penicillin (10,000 U/mL), streptomycin (10,000 μg/mL) and 25 μg/mL amphotericin B as an antifungal agent (Thermo Fisher Scientific, Waltham, MA, USA) [ 28 ]. Primary human osteoblasts were purchased from PromoCell (Heidelberg, Germany) and cultured in DMEM (Invitrogen, Paisley, UK) supplemented with 10% fetal calf serum (FCS, Invitrogen, Paisley, UK), antimycotic and antibiotics (Invitrogen, Paisley, UK) [ 29 ]. The cells were seeded at a density of 1.6 × 10 4 /cm 2 in an appropriate volume of medium and incubated in a humidified atmosphere at 37 °C with 5% CO 2 .…”

Prognostic analysis of percutaneous vertebroplasty (PVP) combined with 125I implantation on lumbosacral vertebral osteoblastic metastases

“…In recent years, percutaneous vertebroplasty (PVP) has become a surgical method for the treatment of osteolytic destruction of bone metastases [19][20][21][22][23]. PVP surgery for osteoblastic metastases is rare [21].…”