Prostate‐specific antigen modulates the osteogenic differentiation of MSCs via the cadherin 11‐Akt axis

Abstract

Background A high prevalence of osteoblastic bone metastases is characteristic of prostate cancer. Prostate‐specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serological marker for prostate cancer. However, whether PSA modulates the osteogenic process remains largely unknown. In this study, we explored the effect of PSA on modulating the osteoblastic differentiation of mesenchymal stem cells (MSCs). In this study, we used flow cytometry, CCK‐8 assay, Alizarin red S (ARS) staining and quantification, alkaline phosphatase (ALP) activity and staining, Western blotting, and quantitative real‐time PCR (qRT‐PCR) to explore the effect of PSA on osteogenic differentiation of MSCs. Results We first demonstrated that although PSA did not affect the proliferation, morphology, or phenotype of MSCs, it significantly promoted the osteogenic differentiation of MSCs in a concentration‐dependent manner. Furthermore, we demonstrated that PSA promoted the osteogenic differentiation of MSCs by elevating the expression of Cadherin 11 in MSCs and, thus, activating the Akt signaling pathway. Conclusions In conclusion, we demonstrated that PSA could promote the osteogenesis of MSCs through Akt signaling pathway activation by elevating the expression of cadherin‐11 in MSCs. These findings imply a possible role of PSA in osteoblastic bone metastases in prostate cancer.

In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer

“…Yet, the benefit of having a mineralized microtissue tissue engineered from a single bone cell type is still important, enabling to decouple the roles of osteoblasts and osteoclasts in bone mCPRC. Osteoclasts are indeed often considered responsible for the initiation of the vicious cycle of metastasis by releasing factors that inducing stem cell osteogenic differentiation ( 4 ) and osteoblast activation ( 11 ). However, as stated by Ark et al , ( 10 ) it is not currently known whether and how osteoclasts or osteoblasts affect enzalutamide resistance and whether the effects of enzalutamide on those cells contribute to drug resistance ( 10 ).…”

“…While none of these androgen-targeted therapies (ATTs) are curative, they do provide survival advantages and are widely clinically used. Androgen signaling is key to all prostate cancer stages ( 3 ), and thus, targeting the androgen axis continues to be the gold standard for recurrent advanced disease ( 4 ), with enzalutamide treatment one of the most used currently ( 5 ), in sequence with cytotoxic chemotherapy and bone-targeting agents ( 2 ). Yet, although recent data suggest that targeting the tumor cells and the bone microenvironment improves survival ( 6 ), the role of the tumor microenvironment as a key modulator of tumor cell response to therapy is still unclear.…”

“…Bone metastases in prostate cancer are predominantly bone forming ( 6 ), referred to as osteoblastic/osteosclerotic, although osteoclasts have been proposed as the key to the initiation of the vicious cycle in mCRPC by releasing growth factors (GFs) such as transforming GF–β and insulin-like GFs (IGFs), which attract prostate cancer cells ( 6 ). In turn, cancer cells are responsible for the establishment of a microenvironment inducing stem cell osteogenic differentiation ( 4 ) and osteoblast activation ( 11 ) by the direct secretion of GFs (IGF, endothelin-1, and platelet-derived GF) as well as by controlling the localization and activity of multiple soluble factors through the production of proteases, including matrix metalloproteinases 7 and 9 ( 12 ). While some mechanisms have been proposed, the factors involved in the cross-talk between cancer cells and the bone microenvironment, especially in the context of ATT and acquired ATT resistance ( 10 ), still have not been identified.…”

AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review

“…Additionally, prostate cancer-secreted CCN3 was shown to mediate RANK upregulation in osteoclast precursors via the FAK/AKT/mitogen-activated protein kinase 11 (p38)/NF-κB axis and, thus, promotes the RANKL-dependent osteoclastogenesis and tumor-induced osteolysis [ 112 ]. On the other hand, the prostate cancer-secreted serine protease prostate-specific antigen (PSA) induces osteogenic differentiation of mesenchymal stem cells via a cadherin 11/AKT axis and, thus, contributes to the formation of osteoblastic lesions [ 135 ]. In summary, much data exists on the role of AKT in the interaction between prostate tumor cells and osteoclasts.…”

miR‑351‑5p aggravates lipopolysaccharide‑induced acute lung injury via inhibiting AMPK

“…Total RNA was extracted from the lungs using TRIzol™ reagent (Thermo Fisher Scientific, Inc.) and used for reverse transcription and cDNA synthesis (36,(43)(44)(45)(46). Next, qPCR was performed using the SYBR Premix Ex Taq kit (Takara Biotechnology Co., Ltd.) on a CFX96 real-time PCR detection system (Bio-Rad Laboratories, Inc.).…”