Total and Free PSA, PCA3, PSA Density and Velocity

Biology

PSA is an androgen-regulated chymotrypsin-like serine protease, part of the family of proteases known as kallikreins encoded by a cluster of genes located on human chromosome 19q13.4, and are thus also called human kallikrein (hK) 3. It is produced in high levels within the prostatic ductal and acinar epithelium, with a 17-amino acid leader sequence (preproPSA) that is cleaved cotranslationally to generate an inactive 244-amino acid precursor protein (proPSA), with seven additional amino acids compared to mature PSA. Generally, proPSA is normally secreted from the prostate luminal epithelial cells, and after its release into the lumen, the proleader part is removed and converted to its active form by the effect of hK-2 and hK-4, which have a trypsin-like activity and are expressed predominantly by prostate secretory epithelium. Other kallikreins, localized in the prostate, such as hK-216 or prostin 17, are involved in the conversion and activation of proPSA. Cleavage of the N-terminal seven amino acids from proPSA generates the active enzyme (PSA), which has a mass of 33 kDa. In the seminal fluid, PSA cleaves the seminogelin I and II, thus promoting the semen liquefaction. The enzymatically active PSA is normally confined within the prostate gland by a tight and orderly prostatic glandular architecture. Consequently, only a few PSA leaks into the circulation, and its serum concentration (<4 μg/L) is a million-fold lower than that in the seminal plasma (0.5–5 g/L). The measurable serum total PSA (tPSA) comprises either a complexed form (cPSA, 70–90%), bound by protease inhibitors (primarily α1-antichymotrypsin) and a noncomplexed form (free PSA, fPSA). fPSA has recently been discovered to exist in at least three molecular forms: proPSA, benign PSA (BPSA), and inactive intact PSA (iPSA), covering approximately 33, 28, and 39% of fPSA, respectively. BPSA is a degraded form of PSA that is identical to the native, mature PSA with 237 amino acids but contains two internal peptide bond cleavages at Lys182 and Lys145. Immunohistochemical studies have shown that BPSA is expressed preferentially in the transitional zone of the prostate and is associated with pathological benign prostate hyperplasia (BPH). iPSA is similar to native PSA but is inactive due to structural or conformational changes. The partial removal of the leader sequence of the preproPSA leads to other truncated forms of proPSA. Hence, theoretically, seven isoforms of proPSA should exist, although only [−1], [−2], [−4], [−5], [−7]proPSA were found, while there is still no evidence of [−3], [−6]proPSA. All these forms of proPSA are enzymatically inactive, but they might play a role in cancer detection, especially [−2]proPSA.