Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABAA R-Dependent TRIM21 Modulation of Src Expression.

Qidong Liu,Yuan Shen,Ping Wang,Chun Cheng,Michael Lanuti,Hui Zheng,Rong Liu,Zhihao Sheng,Zhongcong Xie

doi:10.1002/advs.202102079

Abstract

Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low‐ or standard‐dose propofol to nude mice through tail vein. Propofol‐ or vehicle‐treated tumor cells are also injected to the mice. An in vitro tumor cell–vascular endothelial cell adhesion assay, immunofluorescence, and other methods are employed to assess how propofol affects tumor cell adhesion and extension. Propofol induces more lung tumor metastasis in mice than control. Mechanistically, propofol enhances tumor cell adhesion and extension through GABAAR to downregulate TRIM21 expression, leading to upregulation of Src, a protein associated with cell adhesion. These results demonstrate that propofol may promote tumor metastasis through GABAAR–TRIM21–Src mechanism.

Highlights

Perioperative factors including anesthesia and surgery have been reported to associate with poor prognosis in tumor patients, surgical tumor resection, are critical for tumor metastasis and recurrence.[7]
We found that the propofol-treated tumor cells had increased photon intensity (7.31 ± 0.47 vs 7.98 ± 0.16, P = 0.019, Student’s t-test) (Figure 1g,h) and number of nodules (15.44 ± 7.21 vs 42.33 ± 14.62, P = 0.001, Student’s t-test) (Figure 1i,j) as compared to DMSO-treated tumor cells four weeks after injection
We showed that treatment with standard-dose propofol promoted tumor metastasis to the lungs as compared to low-dose g) Fluorescent micrographs showing adhesion between the human umbilical vein endothelial cells (HUVECs) monolayer and the HCT116 cells with or without Src overexpression. h) Western blot analysis of Src and phosphorylated Src (p-Src) expression in bicuculine-treated HCT116 cells with or without Src overexpression

Summary

Introduction

Perioperative factors including anesthesia and surgery have been reported to associate with poor prognosis in tumor patients, surgical tumor resection, are critical for tumor metastasis and recurrence.[7] In addition, some cell culture studies reported that propofol regulates proliferation, migration, and invasion of tumor cells,[8] these in vitro studies employed a longer. Liu Division of Thoracic Surgery Department of Surgery Massachusetts General Hospital and Harvard Medical School Boston, MA 02114, USA

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Conclusion