Introduction
Ovarian cancer is the sixth most frequently diagnosed cancer and the seventh-highest mortality globally (Parkin, Bray, Ferlay, & Pisani, 2005). There were an estimated more than 295,000 new cases and more than 184,000 deaths of ovarian cancer worldwide in 2018 (Bray et al., 2018). The treatments for ovarian cancer include surgery, chemotherapy, and radiotherapy. Among them, surgery remains the frontline therapy for ovarian cancer patients, as the tumour resection at the early stage can be very effective (Wyld, Audisio, & Poston, 2015). However, ovarian cancer recurrence following surgery is still a leading cause of death (Saphner, Tormey, & Gray, 1996; Zhu et al., 2011).
Many risk factors affect cancer recurrence, and one of them may be the choice of anaesthetics and anaesthesia techniques (Horowitz, Neeman, Sharon, & Ben-Eliyahu, 2015). In an in vitro study, oestrogen receptor-positive or negative breast cancer cells were exposed to sevoflurane, and the proliferation and migration of both types of cancer cells were increased by sevoflurane (Ecimovic, McHugh, Murray, Doran, & Buggy, 2013). An previous publication from our laboratory demonstrated that sevoflurane increased the migration of ovarian cancer cellsvia upregulating VEGFA, MMP11, CXCR2, and TGF-βgene expressions (Iwasaki et al., 2016). In contrary, propofol was reported to have an “anti-tumour” property; for example, our previous study demonstrated that propofol inhibited the proliferation and migration of prostate cancer cells (Huang et al., 2014). Clinically, a retrospective study reported that patients, who had surgery for the breast, colonic or rectal cancer, were under propofol-based total intravenous anaesthesia or sevoflurane inhalational anaesthesia and their overall one-year and five-year survival rates were higher with propofol anaesthesia (Enlund et al., 2014). However, the underlying mechanisms are unknown.
Glucose is taken up by cancer cells through glucose transporter 1 (GLUT1) and transformed to pyruvate, which is converted to lactate rather than enters mitochondria via mitochondrial pyruvate carrier 1 (MPC1) to be utilised by TCA cycle (Pezzuto, D’Ascanio, Ricci, Pagliuca, & Carico, 2020; Zou et al., 2019). Glutamine can be transformed to be glutamate under the catalysation of glutamate dehydrogenase 1 (GLUD1) for using in the TCA cycle which generates crucial intermediates for cancer growth and survival (Craze et al., 2019). Such process is named as glutaminolysis for which GLUD1 is the key enzyme that locates in the inner membrane of mitochondria. Any factors that affect the GLUD1 expression and activity may interfere cancer cell survival (Son et al., 2013).
The transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α) plays a key role of the development of many tumour types, including breast, colonic and lung cancer (Zhao, Iwasaki, Yang, Savage, & Ma, 2014) whilst the cellular signalling Erk1/2 pathway can regulate HIF-1α (Karagiota, Kourti, Simos, & Mylonis, 2019). Several regulators can regulate the signalling pathway of Erk1/2 and one of these regulators is the pigment epithelium-derived factor (PEDF), a member of the serine protease inhibitor family. The therapeutic values of PEDF were found for choroidal neovascularisation, heart disease and cancer (Filleur, Nelius, de Riese, & Kennedy, 2009). Besides the upstream signalling of HIF-1α, the downstream effectors of HIF-1α might also involve in the ovarian cancer malignancy. C-X-C motif chemokine 12 (CXCL12), also called stromal cell-derived factor 1 (SDF1), is originally correlated with the activity of leukocytes and its receptor is C-X-C chemokine receptor type 4 (CXCR4), also named as fusin or cluster of differentiation 184 (CD184) (Takano et al., 2014). It was found that CXCL12-CXCR4 was overexpressed in a variety of cancer types, and is involved in the progression of tumours (Scala et al., 2020).
In the current study, we hypothesised that unlike propofol, sevoflurane might upregulate the expressions of GLUT1, MPC1, and GLUD1, which increases the metabolism of ovarian cancer cells. The increased uptake of glucose inhibits the expression of PEDF and, in turn, upregulates p-Erk1/2, HIF-1α, CXCL12, and CXCR4. The alterations of metabolism and molecular entities by anaesthetics such as sevoflurane and propofol might change the malignancy of ovarian cancer cells.