Altered levels of acid, basic, and neutral peptidase activity and expression in human clear cell renal cell carcinoma

Abstract

Peptides play important roles in cell regulation and signaling in many tissues and are regulated by peptidases, most of which are highly expressed in the kidney. Several peptide convertases have a function in different tumor stages, and some have been clearly characterized as diagnostic and prognostic markers for solid tumors, including renal cancer; however, little is known about their in vivo role in kidney tumors. The present study compares the activity of a range of peptidases in human tumor samples and nontumor tissue obtained from clear cell renal cell carcinoma (CCRCC) patients. To cover the complete spectrum and subcellular distribution of peptide-converting activity, acid, neutral, basic, and omega activities were selected. CCRCC displays a selective and restricted pattern of peptidase activities. Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopeptidase N decreases (t = 6,664 vs. n = 33,381 UP/mg protein; P < 0.001). Aminopeptidase B activity of the particulate fraction in tumors decreases (t = 2,399 vs. n = 13,536 UP/mg protein; P < 0.001) compared with nontumor tissues, and aspartyl-aminopeptidase activity decreases significantly in CCRCC (t = 137 vs. n = 223 UP/mg protein; P < 0.05). Soluble and particulate pyroglutamyl peptidase I activities, aminopeptidase A activity, and soluble aminopeptidase B activity do not vary in renal cancer. The relative expression for the aforementioned peptidases, assayed using quantitative RT-PCR, increases in CCRCC for aminopeptidases B (1.5-fold) and A (19-fold), aspartyl-aminopeptidase (3.9-fold), puromycin-sensitive aminopeptidase (2.5-fold), and pyroglutamyl peptidase I (7.6-fold). Only aminopeptidase N expression decreases in tumors (1.3-fold). This peptidase activity profile in the neoplastic kidney suggests a specific role for the studied convertases and the possible involvement of an intracrine renin-angiotensin system in the pathogenesis of CCRCC.

Acid, basic, and neutral peptidases present different profiles in chromophobe renal cell carcinoma and in oncocytoma

“…However, the mRNA levels of Asp-AP, APA, APB, and PGI were not in concordance with our data on peptidase activity. We reported a similar pattern of expression in our previous study on CCRCC (37).…”

“…Renal parenchyma is a tissue very rich in both soluble and particulate peptidases (24,31). We previously reported significant alterations in the activity and the expression profiles of several of the aforementioned enzymes when human samples of primary CCRCC were compared with their surrounding uninvolved tissue (37). Interestingly, with the exception of puromycin-sensitive aminopeptidase (PSA; EC 3.4.11.14), a soluble activity which increased in CCRCC, all the peptidases showing alterations of activity in tumor cells were downregulated.…”

Proteomics Characterization of the Cytotoxicity Mechanism of Ganoderic Acid D and Computer-automated Estimation of the Possible Drug Target Network

“…Note that aminopeptidase B was predicted to be able to bind directly with GAD in the INVDOCK analysis of present study. And it was reported that the aminopeptidase B activity was decreased in human renal cell carcinoma samples compared with non-tumor tissues (49). The increase of aminopeptidase B protein expression in GAD-treated HeLa cells may play an important role in the cytotoxicity of GAD.…”

Mass spectrometry of peptides and proteins from human blood

“…There may be an impression that blood exopeptidases are non-specific enzymes that are not under differential regulation between physiological states (Sanderink, Artur, & Siest, 1988;Diamandis, 2006a). However there are multiple reports of disease specific exopeptidase activity as a markers or mechanisms of disease in blood, tissues and cells (Elgun, Karaayvaz, & Durak, 1997;Simaga et al, 1998;Martinez et al, 1999;van Hensbergen et al, 2002;Davis et al, 2005;Varona et al, 2007). Furthermore a statistical model of peptidome degradation using the Metropolis-Hastings algorithm for Bayesian inference of model parameters and other mathematical models supported the hypotheses of disease-specific exopeptidase activity Kluge, Gambin, & Niemiro, 2009).…”