Molecular and cellular pharmacologyPropofol attenuates pancreatic cancer malignant potential via inhibition of NMDA receptor
Introduction
Cancer remains one of the main causes of death worldwide and surgery is the prior option for most solid tumor treatment. However surgical stress could affect the immune and neuroendocrine systems, and induce inadvertent seeding of tumor cells during surgery (Boomsma et al., 2010, Camara et al., 2006, Mori et al., 1996, Tsuchiya et al., 2003), thus affecting the prognosis of the patients. Despite great progress made in surgical skills and perioperative care, the overall survival rate in patients with pancreatic cancer is still low. Moreover, pancreatic cancer surgery duration is usually as long as 6–7 h (Gangavatiker et al., 2011, Okano et al., 2015), which allows the anesthesiologist to possess more time to participate in the treatment procedure intra-operatively.
Elevation of hypoxia-inducible factor 1α (HIF-1α) expression has been found in a variety of human cancers (Talks et al., 2000). As a directly master control of the expression of numbers of genes, HIF-1α up-regulation is related to tumor growth (Terraneo et al., 2010, Wang et al., 2011), vascularization (Ban et al., 2010) and migration (Burrows et al., 2011), thus leading to poor patient outcome. Moreover, studies have indicated that ERK (Liu et al., 2010) and AKT (Huang et al., 2014) lies upstream of HIF-1α, and activation of ERK or AKT could activate HIF-1α (Huang et al., 2014, Liu et al., 2010).
Large amount of clinical research indicate that anesthesia methods could influence prognosis of cancer patients (Biki et al., 2008, Christopherson et al., 2008, Exadaktylos et al., 2006, Lin et al., 2011). However, (1) all this data are retrospective and therefore provide very weak evidence, and (2) there are also a large number of studies that cannot show any effect of anesthetics on cancer. Recent studies indicated that anesthetics could affect cancer cells malignant potential (Benzonana et al., 2013, Huang et al., 2014). Inhalation anesthetics and propofol were reported to play an opposite role on cancer biology. Isoflurane augmented tumor growth in human cancer cells, while propofol inhibited cancer cells proliferation (Benzonana et al., 2013; Huang et al., 2014). Propofol is a commonly used intravenous anesthetic in clinic. It has been proposed that propofol could inhibit cancer cells malignant potential via inhibiting HIF-1α expression (Huang et al., 2014). However, the mechanism has not been elucidated. In the present study, we mainly focus on the mechanism by which propofol down-regulates HIF-1α expression and malignant potential in pancreatic cancer cells.
Section snippets
Cell culture and reagent
Miapaca-2, Panc-1 and Panc02, purchased from the American Type Culture Collection (ATCC), were cultured in DMEM with 10% fetal bovine serum at 37 °C in a humidified 5% CO2 incubator. Cells were sub-cultured when reaching 90% confluence.
KN93, an inhibitor of Ca2+/calmodulin dependent protein kinases (CaMK II), MK801, an inhibitor of N-Methyl-D-aspartate (NMDA) receptor, and rapastinel, an activator of NMDA receptor, were purchased for Sigma (St. Louis, MO). The substances employed in the present
Propofol inhibits VEGF expression and cells migration in Miapaca-2 and Panc-1 cells
In Miapaca-2 and Panc-1 cells, propofol inhibited VEGF expression (Fig. 1A, B) and migration (Fig. 1C) in a concentration-dependent manner. Compared with control group, incubation of cells with 50 μM propofol significantly attenuated VEGF expression and cells migration in Miapaca-2 and Panc-1 cells (Fig. 1). Moreover, the propofol solvent dimethyl sulfoxide (DMSO) did not affect VEGF expression and cells migration.
Propofol inhibits HIF-1α expression, ERK and AKT phosphorylation in Miapaca-2 and Panc-1 cells
In Miapaca-2 and Panc-1 cells, propofol inhibited HIF-1α expression (Fig. 2A, B),
Discussion
In the present study we proposed that propofol via inhibiting NMDA receptor, attenuated intracellular Ca2+ concentration, CaMK II, ERK, AKT phosphorylation and HIF-1α expression, thus suppressing VEGF expression, cells migration and the growth of tumor.
HIF-1α has been indicated to activate a spectrum of downstream genes to promote cell proliferation (Terraneo et al., 2010, Wang et al., 2011), angiogenesis (Ban et al., 2010) and migration (Burrows et al., 2011). Upregulation of HIF-1α expression
Conclusions
In summary, the present study indicated that propofol attenuated Ca2+ concentration, inhibited CaMK II, ERK and AKT phosphorylation, down-regulated HIF-1α expression, and eventually inhibited VEGF expression, cells migration and the growth of tumor. The anti-tumor effect of propofol may be achieved via inhibition of NMDA receptor.
Declaration
Xiangyuan Chen, Qichao Wu, Li You, Sisi Chen, Minmin Zhu and Changhong Miao have none conflicts of interest.
Acknowledgements
We thank Zhen Wang (Fudan University Shanghai Cancer Center, Shanghai, China) for assistance in experimental technologies.
This project is supported by Shanghai Charity Cancer Research Center (No. HYXH1407).
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