Premium
PSA‐alpha‐2‐macroglobulin complex is enzymatically active in the serum of patients with advanced prostate cancer and can degrade circulating peptide hormones
Author(s) -
Kostova Maya B.,
Brennen William Nathaniel,
Lopez David,
Anthony Lizamma,
Wang Hao,
Platz Elizabeth,
Denmeade Samuel R.
Publication year - 2018
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23539
Subject(s) - prostate cancer , prostate , prostate specific antigen , medicine , endocrinology , cancer , peptide , serine protease , protease , chemistry , enzyme , biochemistry
Background Prostate cancer cells produce high levels of the serine protease Prostate‐Specific Antigen (PSA). PSA is enzymatically active in the tumor microenvironment but is presumed to be enzymatically inactive in the blood due to complex formation with serum protease inhibitors α‐1‐antichymotrypsin and α‐2‐macroglobulin (A2M). PSA‐A2M complexes cannot be measured by standard ELISA assays and are also rapidly cleared from the circulation. Thus the exact magnitude of PSA production by prostate cancer cells is not easily measured. The PSA complexed to A2M is unable to cleave proteins but maintains the ability to cleave small peptide substrates. Thus, in advanced prostate cancer, sufficient PSA‐A2M may be in circulation to effect total A2M levels, levels of cytokines bound to A2M and hydrolyze small circulating peptide hormones. Methods Total A2M levels in men with advanced prostate cancer and PSA levels above 1000 ng/mL were measured by ELISA and compared to controls. Additional ELISA assays were used to measure levels of IL‐6 and TGF‐beta which can bind to A2M. The ability of PSA‐A2M complexes to hydrolyze protein and peptide substrates was analyzed ± PSA inhibitor. Enzymatic activity of PSA‐A2M in serum of men with high PSA levels was also assayed. Results Serum A2M levels are inversely correlated with PSA levels in men with advanced prostate cancer. Il‐6 Levels are significantly elevated in men with PSA >1000 ng/mL compared to controls with PSA <0.1 ng/mL. PSA‐A2M complex in serum of men with PSA levels >1000 ng/mL can hydrolyze small fluorescently labeled peptide substrates but not large proteins that are PSA substrates. PSA can hydrolyze small peptide hormones like PTHrP and osteocalcin. PSA complexed to A2M retains the ability to degrade PTHrP. Conclusions In advanced prostate cancer with PSA levels >1000 ng/mL, sufficient PSA‐A2M is present in circulation to produce enzymatic activity against circulating small peptide hormones. Sufficient PSA is produced in advanced prostate cancer to alter total A2M levels, which can potentially alter levels of a variety of growth factors such as IL‐6, TGF‐beta, basic FGF, and PDGF. Alterations in levels of these cytokines and proteolytic degradation of small peptide hormones may have profound effect on host‐cancer interaction.