Mitogenic Response of Osteoblast Cells to Prostate-Specific Antigen Suggests an Activation of Latent TGF-β and a Proteolytic Modulation of Cell Adhesion Receptors

doi:10.1006/bbrc.1993.1506

Biochemical and Biophysical Research Communications

Volume 192, Issue 2, 30 April 1993, Pages 940-947

https://doi.org/10.1006/bbrc.1993.1506 Get rights and content

Abstract

During studies of mitogens in prostate, PSA quantities as low as 2.5 ng/mL caused cultured osteoblast cells to proliferate beyond controls (p=<0.05). Investigation of this novel mitogenicity suggested the use of several mechanisms by PSA, namely: 1) the activation of latent hTGF-β in PC-3 conditioned medium, PSA treated conditioned medium stimulated DNA uptake in UMR-106 cells to 78% of acid treated conditioned medium, while DNA incorporation was less than controls with anti-hTGF-β neutralizing IgG; and 2) the proteolytic modulation of cell surface receptors with temporary contact inhibition, PSA significantly stimulated cell detachment while hTGF-β enhanced cell attachment of confluent Saos-2 cells above controls. Clinically, these results suggest that PSA may provide a mechanism for both tumor spread and the osteoblastic metastasis so common to prostate cancer.

References (0)

Cited by (170)

Circulating Peptidome and Tumor-Resident Proteolysis
2017, Enzymes
Citation Excerpt :
Studies indicate that inactivation of autophagy-regulating genes like beclin1, a component of a phosphatidylinositol-3-kinase complex that controls vesicle trafficking, can promote tumorigenesis, while overexpression of these genes blocks tumor development, implying that autophagy functions as a tumor-suppressive mechanism. Consistent with this hypothesis, mice deficient in autophagin-3 (Atg4C), which appears to regulate autophagy initiation under conditions of physiological stress, exhibit increased susceptibility to carcinogen-induced fibrosarcoma development [28]. However, other studies have suggested that expression of specific autophagins may positively regulate tumor progression.
Mammalian proteases segregate into several distinct protein families that employ different functional domains to hydrolyze peptides bonds with different specificities and affinities. These enzymes play central roles in critical cellular and systemic processes, including regulation of cell growth, differentiation, homeostasis, and apoptosis; and cancer initiation, progression, and metastasis. Human proteases segregate into five distinct catalytic classes; the metalloprotease, serine protease, and cysteine protease families have the most members, while the aspartic and threonine peptidase families have relatively few examples. Section 1 discusses the five different types of human proteases and summarizes some of their known functions during tumorigenesis, migration, and metastasis. Section 2 focuses on how cancer degradomes, defined as all the proteases, protease inhibitors, and protease substrates regulated by a given cancer, affect cancer promotion and suppression, and current approaches for degradome profiling. Protein degradation products generated during cancer progression, invasion, and metastasis alter the tumor microenvironment to influence these processes. These cancer-associated protein degradation profiles (aka tumor peptidomes) represent a potentially rich pool of candidates for cancer biomarker discovery. Section 3 focuses on the benefits and challenges associated with peptidome studies, and methods employed to conduct them.
Section 4 discusses recent studies that use circulating peptides as cancer biomarkers, and how the abundance of peptides reflects the activity of their source proteases during cancer progression. We hope this chapter will convey a good sense of current research on how cancer-associated proteases, degradomes, and their resulting peptidomes can improve our knowledge of cancer biology, improve diagnosis and evaluation, and inspire new ideas in this and related research areas.
Bones and Cartilage: Developmental and Evolutionary Skeletal Biology
2015, Bones and Cartilage: Developmental and Evolutionary Skeletal Biology
Effect of chronic Sildenafil treatment on the prostate of C57Bl/6 mice
2014, Tissue and Cell
Citation Excerpt :
PSA is thought to cleave insulin-like growth-factor-binding protein 3 (IGFBP3), thereby liberating insulin-like growth-factor 1 (IGF1), which is a mitogen to the prostatic stromal and epithelial (Cohen et al., 1992; Sutkowski et al., 1999; Djavan et al., 2001). PSA can also activate latent transforming growth factor (TGF)-β, which can stimulate cell detachment and facilitate the spread of tumor-cells (Killian et al., 1993). Based on these observations, the expression of TGF prostatic tissue was evaluated by western blot.
Sildenafil is a potent and selective inhibitor of phosphodiesterase-5 (PDE5) and is considered first-line therapy for erectile dysfunction. Nowadays, Sildenafil is used extensively throughout the world on patients with pulmonary hypertension. However, few studies have evaluated the possible side effects of chronic Sildenafil treatment on the male reproductive system, specifically in the prostate. In the present study, it was demonstrated via morphological and ultrastructural analysis that chronic treatment with Sildenafil induced an enhancement of the glandular activity of the prostate. In addition, mice treated with Sildenafil showed a significant increase in testosterone serum levels. However, no statistically significant differences were observed in nitric oxide serum levels, or in sGC, eNOS, PSA and TGF-β prostatic expression. In conclusion, the present study suggests that chronic use of Sildenafil does not cause evident prostatic damage, and therefore, can be used pharmacologically to treat a variety of disorders.
Tumor Microenvironment, Clinical Features, and Advances in Therapy for Bone Metastasis in Gastric Cancer
2022, Cancers
A Suite of Activity-Based Probes to Dissect the KLK Activome in Drug-Resistant Prostate Cancer
2021, Journal of the American Chemical Society
Klk4 induces anti-tumor effects in human xenograft mouse models of orthotopic and metastatic prostate cancer
2020, Cancers

View all citing articles on Scopus

View full text

Regular ArticleMitogenic Response of Osteoblast Cells to Prostate-Specific Antigen Suggests an Activation of Latent TGF-β and a Proteolytic Modulation of Cell Adhesion Receptors

Abstract

Regular Article
Mitogenic Response of Osteoblast Cells to Prostate-Specific Antigen Suggests an Activation of Latent TGF-β and a Proteolytic Modulation of Cell Adhesion Receptors