In the current investigation we studied the effect of propof

In the current investigation, we studied the effect of propofol on prostate cancer cells. Propofol is one of the most commonly used drugs in the critical care setting and for the induction of general anesthesia and moderate and deep sedation intraoperatively. Recent studies indicated that propofol exerts antitumor effects in some cancers. For example, propofol induces apoptosis in cervical cancer dl 473 via the mammalian target of rapamycin (mTOR) pathway (Zhang et al., 2015). However, another study demonstrated that propofol induces proliferation in gallbladder cancer cells (Zhang et al., 2012). Therefore, the effect of propofol appears to vary according to cancer cell type. Although the effect of propofol in prostate cancer remains unclear, one study demonstrated that propofol modulated the malignancy of PC3 prostate cancer cells (Huang et al., 2014). Androgen receptor is essential for prostate cancer progression, but the influence of general anesthetics on androgen receptor activity remains unknown. Therefore, we explored the effects of propofol in prostate cancer cells, with a specific focus on androgen receptor activity.
Material and methods
Results
Discussion In the current study, we found that propofol significantly inhibited DHT-induced androgen receptor -dependent gene expression and suppressed nuclear androgen receptor protein levels in LNCaP cells. The development and proliferation of prostate cancer is strongly influenced by the transactivation of androgen receptor (Kim and Coetzee, 2004, Zhao et al., 2014). Therefore, inhibiting androgen receptor activity is predicted to attenuate prostate cancer progression. We demonstrated that the viability of LNCaP cells was significantly suppressed by long-term exposure to propofol. Previous studies reported that propofol exerts antitumor effects in vitro in various types of cancer cells including osteosarcoma (Xu et al., 2016), pancreatic (Chen et al., 2017), lung (Cui et al., 2014), and cervical cancer cells (Zhang et al., 2015). However, the mechanism mediating the anti-cancer effects of propofol differed in each context. In contrast, volatile anesthetics have been reported to promote tumor cell progression. For example, isoflurane increases the malignant potential of ovarian cancer (Luo et al., 2015) and glioblastoma cells (Zhu et al., 2016). However, in the present study, both isoflurane and propofol suppressed the expression of androgen receptor-dependent genes and nuclear androgen receptor protein levels in LNCaP cells, suggesting that both types of general anesthetics suppress prostate cancer proliferation by inhibiting androgen receptor activity. Clinical studies comparing general anesthesia plus epidural anesthesia with general anesthesia alone have reported conflicting results. For example, Scavonetto et al. reported that general anesthesia alone was associated with an increased risk of systemic progression (hazard ratio [HR] = 2.81) and higher overall mortality (HR = 1.32) compared with the combination of general and epidural anesthesia in more than 3000 patients with prostate cancer (Scavonetto et al., 2014). In contrast, another study reported that outcomes in prostate cancer patients were not affected by adjunctive epidural anesthesia (Tsui et al., 2010). Furthermore, a recent study detected no significant difference between general anesthesia and epidural anesthesia in prostatectomy outcomes (Sprung et al., 2014). Therefore, the differential effects of various anesthesia techniques in prostate cancer patients remains controversial, despite evidence from multiple studies demonstrating that local anesthesia inhibits cancer progression in vitro (Kim et al., 1997, Werdehausen et al., 2009). The anti-androgen receptor activity of general anesthetics observed in the current study might be the reason why local anesthesia did not demonstrate significant effects in multiple clinical studies. Similar to androgen receptor activity, hypoxia is another key mediator of prostate cancer (Fraga et al., 2015). Most locally advanced solid cancers contain hypoxic regions, and hypoxia contributes to more aggressive and metastatic phenotypes (Greco et al., 2003, Hockel and Vaupel, 2001). Most genes essential for the adaptation of cancer cells to hypoxic conditions are regulated by the transcriptional factor HIF-1 (Semenza, 2003). HIF-1 is composed of an oxygen-sensitive α subunit (HIF-1α) and a constitutionally expressed β subunit (HIF-1β) (Semenza et al., 1991). Under normal conditions, HIF-1α is rapidly degraded via the ubiquitin-proteasome pathway. However, under hypoxic conditions, HIF-1α is stabilized and transported to the nucleus where it forms a dimer with HIF-1β (Wang et al., 1995). HIF-1α expression is associated with tumor growth, progression, metastasis, and resistance to radiotherapy and chemotherapy (Deep et al., 2017, Lu and Kang, 2010). We found that propofol significantly suppressed nuclear HIF-1 levels and the expression of HIF-dependent genes in hypoxic conditions with or without DHT stimulation. As HIF-1 expression correlates with prostate cancer malignancy (Milosevic et al., 2012), the inhibitory effect of propofol on HIF-1 can provide therapeutic benefits. However, isoflurane has been reported to upregulate HIF-1α protein levels in various types of cancer cells, including prostate cancer cells (Huang et al., 2014). In a retrospective study comparing volatile anesthesia and propofol in cancer-related surgery in a total of 11,395 patients, mortality was 50% greater with volatile anesthesia compared with propofol-based anesthesia (Wigmore et al., 2016). This difference might be associated with the differential effects of volatile anesthetics and propofol on HIF-1. However, a large-scale study comparing propofol-based and volatile anesthetic-based approaches is required to clarify this issue.