Differential role of intravenous anesthetics in colorectal cancer progression: implications for clinical application

Abstract

Anesthetics are unavoidable to colorectal cancer (CRC) patients who underwent surgical treatment. Thus, the molecular mechanisms underlying the role of the intravenous anesthetics in CRC metastasis are still unclear. In this study, the effects of intravenous anesthetics, such as propofol, etomidate and dexmedetomidine, on cell migration were determined. The migration of CRC cells was inhibited by propofol in vitro, but not in vivo. Etomidate, however, promoted the migration of CRC cells both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) mediated the promotive effect of propofol and etomidate on the migration of CRC cells through PI3K/AKT signaling pathway. Dexmedetomidine alone or in combination with propofol or etomidate had minor effect on the migration of CRC cells. These findings indicate that propofol inhibites CRC cell migration in vitro. Etomidate playes a role for prompting CRC metastasis progression by activating (PI3K)/AKT signaling and inducing EMT. It provides an important hint for the clinical application of these anesthetics.

Keywords: colorectal cancer; dexmedetomidine; epithelial-mesenchymal transition; etomidate; propofol.

Conflict of interest statement

CONFLICTS OF INTEREST

The authors have declared that no conflicts of interest exists.

Figures

Figure 1. Chemical structure of propofol (A), etomidate (B) and dexmedetomidine (C)

Figure 2. The effects of propofol, etomidate and dexmedetomidine on the migration ability of CRC cells

(A) Representative figures and data of transwell assay for SW480 and HCT116 cells treated with 2 and 4 μg/ml of propofol for 24 h. (B) Representative figures and data of transwell assay for SW480 and HCT116 cells treated with 2 and 4 μg/ml of etomidate for 24 h. (C) Representative figures and data of transwell assay for SW480 and HCT116 cells treated with 100 and 200 μg/ml of dexmedetomidine for 24 h. Each bar represented the mean ± SD. The results were reproduced in three independent experiments. The asterisk (*) indicates P < 0.05. The asterisk (**) indicates P < 0.01.

Figure 3. Propofol decreases and etomidate increases the migration ability of CRC cells

(A) Representative figures and data of transwell assay for SW480 and HCT116 cells treated with 100 μg/ml of dexmedetomidine in combination with 2 or 4 μg/ml of propofol for 24 h. (B) Representative figures and data of transwell assay for SW480 and HCT116 cells treated with 100 μg/ml of dexmedetomidine in combined with 2 or 4 μg/ml of etomidate for 24 h. Each bar represented the mean ± SD. The results were reproduced in three independent experiments. The asterisk (*) indicates P < 0.05. The asterisk (**) indicates P < 0.01.

Figure 4. Propofol decreases and etomidate increases AKT activation and epithelial-mesenchymal transition (EMT)

(A) Western blotting analysis of EMT markers and phosphorylated AKT in SW480 and HCT116 cells treated with 100 μg/ml of dexmedetomidine in combined with 2 or 4 μg/ml of propofol for 24 h. (B) Western blotting analysis of EMT markers and phosphorylated AKT in SW480 and HCT116 cells treated with 100 μg/ml of dexmedetomidine in combined with 2 or 4 μg/ml of etomidate for 24 h. Representative figures were shown. The results were reproduced in 3 independent experiments.

Figure 5. AKT activation is responsible for the promotive effect of etomidate on cell migration

(A) Representative figures and data of transwell assay for indicated cells. Each bar represented the mean ± SD. The results were reproduced in three independent experiments. The asterisk (*) indicates P < 0.05. The asterisk (**) indicates P < 0.01. (B) Western blotting analysis of EMT markers and phosphorylated AKT in indicated cells. Representative figures were shown. The results were reproduced in 3 independent experiments.

Figure 6. Etomidate, but not propofol, promotes CRC progression in vivo

Mice were anesthesia with an intraperitoneal injection of propofol 20 mg/kg or etomidate 30 mg/kg. Tumor cells were injected into nude mice through the tail vein to evaluate the lung homing potential of cells. The number of metastatic lung nodules in individual mice was counted under the microscope. The magnification areas indicated metastatic nodes in the lung.