Effect of dexamethasone on extracellular secretion of cystatin C in cancer cell lines

Abstract

Abstract. The aim of the present study was to investigate dexamethasone (DEX)-induced secretion of cystatin C (Cys C) and the effect of cisplatin (CDDP) and 5-fluorouracil (5-FU) on Cys C secretion in human cancer cell lines. KYSE150, A549 and Caki-2 human cancer cell lines were cultured on plastic dishes and treated with DEX (100 nM) for 24, 48 and 72 h. KYSE150 cells were co-treated with DEX, CDDP (10 µM), and 5-FU (2 µM). The effects of DEX, CDDP and 5-FU on cell viability were evaluated. Results showed Cys C secretion levels in the culture medium of DEX-treated KYSE150 cells to be 1.8-to 2.3-fold higher compared to those in the culture medium of control cells. A similar tendency was observed in A549 cells at all the time points, whereas a significant increase in the Cys C secretion by Caki-2 cells was observed only 24 h after DEX treatment. Regarding KYSE150 cells, the secretion of Cys C was also enhanced by co-treatment of CDDP or 5-FU with DEX, although it was not affected by the co-administration of DEX and mifepristone, a glucocorticoid receptor antagonist. At concentrations that are typically used in esophageal cancer chemotherapy, CDDP and 5-FU demonstrated a moderate level of cytotoxicity in KYSE150 cells in contrast to DEX. These findings suggested that DEX has the potential to enhance the extracellular secretion of Cys C in esophageal cancer cells, possibly due to the transcriptional regulation mediated by glucocorticoid receptor activity. IntroductionCystatin C (Cys C) is a non-glycosylated cationic 13.3-kDa protein belonging to the cystatin superfamily of cysteine protease inhibitors (1-3). Cys C is produced by nucleated cells and is secreted into the blood at a constant rate (1-3). It is freely filtered through the glomerular membrane, completely re-absorbed and then catabolized in the proximal tubular cells (1-3). Thus, similarly to creatinine, the biological fate of Cys C is a good endogenous marker of the glomerular filtration rate (GFR).In patients with esophageal cancer, cisplatin (CDDP) is used as a neoadjuvant or as a post-operative adjuvant chemotherapy in combination with continuous infusion of 5-fluorouracil (5-FU) (4,5). When CDDP-based chemotherapy is administered, antiemetic drugs, such as dexamethasone (DEX), 5-HT 3 serotonin receptor antagonists or aprepitant are administered to prevent treatment-associated nausea and vomiting (6). A transient elevation was previously reported in serum Cys C concentration during the perioperative chemotherapy period in patients with esophageal cancer. We suggested that renal function estimates determined on the basis of serum Cys C levels during this treatment period might be misleading (7).To understand the effect of DEX and other drugs in detail, it is crucial to investigate the renal effects associated with serum Cys C concentration. The aim of this study was to investigate the ability of DEX to induce Cys C secretion in human cancer cell lines, as well as the effect of CDDP, 5-FU and mifepristone (RU-486) on Cys C secretion. Materials and metho...

Serum cystatin C is a useful biomarker but not superior to serum creatinine assessment for the diagnosis of acute kidney injury in septic children: a prospective cohort study

“…While cystatin C is a sensitive and specific marker for the early diagnosis of sepsis-associated AKI, it is not superior to serum creatinine. There are several limitations to this study: 1) it is a single center study and includes a relatively small group of patients; 2) the study only included patients with sepsis; however, the inclusion of patients without sepsis would further enhance our understanding of the relationship between sepsis and levels of cystatin C; and 3) it was beyond the scope of the study to address factors that can affect levels of cystatin C level such as serum insulin [32], steroid therapy [33], and hypothyroidism [34].…”

Changes in blood concentrations of trace metals in cancer patients receiving cisplatin-based chemotherapy

“…2, 3, 4A and 5). In patients receiving CDDP-based chemotherapy, antiemetic therapeutic agents, including dexamethasone are administered to prevent treatment-associated nausea and vomiting (24), while dexamethasone has the potential to induce the secretion of cystatin C from cancer cell lines (25,26). It was reported that an increase in serum Fe levels and a decrease in total Fe binding capacity calculated based on serum transferrin levels were observed only during an anti-inflammatory period induced by the administration of prednisolone in an experimental dog study (27).…”

Dexamethasone Modifies Cystatin C-Based Diagnosis of Acute Kidney Injury During Cisplatin-Based Chemotherapy

“…In vitro evidence suggests that corticosteroids increase promoter-mediated transcription of the CysC gene in malignant and non-malignant cells [18, 32]. Longitudinal studies in adults have demonstrated increased pCysC values with chronic or incident corticosteroid use discordant with sCr or measured GFR [8, 14, 16].…”

“…In our study baseline eGFR was similar with sCr and pCysC, suggesting minimal baseline effect on either marker due to the underlying malignancy. In vitro , CysC secretion is not affected by cisplatin [18], but the effect of other anti-emetics on CysC production or release is unknown. In vitro , CysC transcription is increased in numerous cancer cell lines [38, 39], and in some patients with malignancy there is increased pCysC [40, 41], which has generally correlated with burden of disease [42, 43].…”

“…A particular concern in this setting is the corticosteroid based anti-emetic therapy and hydration that routinely accompanies cisplatin. Hydration affects the kinetics of sCr and pCysC [8-10] and corticosteroids can increase production of CysC [11-18]. …”