Inhibition of SUMO2/3 antagonizes isoflurane‑induced cancer‑promoting effect in hepatocellular carcinoma Hep3B cells

Abstract

Surgery for patients with complicated liver cancer often results in a long exposure to anesthesia with an increase in side effects. Continued long-term exposure to isoflurane may promote liver cancer progression. Small ubiquitin-like modifier (SUMO) 2 and 3, also known as SUMO2/3, conjugates to substrate proteins when cells undergo acute stress. However, whether or not SUMO2/3 is involved in isoflurane-mediated liver cancer progression is unknown. In the present study, hepatocellular carcinoma (HCC) cells were exposed to 2% isoflurane for 12 h, followed by 36 h of drug withdrawal, and the formation of SUMO2/3 conjugates and cancer behavioral characteristics were studied. The results demonstrated that the formation of SUMO2/3 conjugates was significantly increased following HCC cells being exposed to isoflurane for 0.5 h, and continued to increase for 48 h, even after the drug had been withdrawn. Furthermore, isoflurane-exposed HCC cells exhibited increased proliferation and invasion activity during the subsequent observation period. SUMO specific protease 3 (SENP3), which inhibits the binding of SUMO2/3 to its target proteins, was overexpressed and it was discovered that isoflurane-induced SUMOylation was significantly inhibited, and accordingly, the proliferation and invasion abilities of HCC cells were decreased to a certain extent. These findings indicated that SUMO2/3 is involved in the progression of HCC cells, at least in the Hep3B cell line, induced by the anesthetic isoflurane, and that inhibition of SUMO2/3 may antagonize the response. These results provided a novel target for decreasing the adverse reactions occurring in patients with HCC during anesthesia, particularly those who are exposed to isoflurane for long periods of time.

FEN1 upregulation mediated by SUMO2 via antagonizing proteasomal degradation promotes hepatocellular carcinoma stemness

“…Additionally, literature cites SUMO2/3 as a pivotal agent driving colorectal cancer progression and oxaliplatin resistance by orchestrating the sumoylation modification of the DNA assembly constituent, Ku80 [56] . Recent revelations align with our experimental evidence, advocating that SUMO2 exerts a positive regulatory influence on hepatocellular carcinoma progression [ 57 , 58 ]. Concurrently, sumoylation modifications have been firmly established as regulators of CSC stemness [ 15 , 17 ].…”

Long-term effect of anesthesia choice on patients with hepatocellular carcinoma undergoing open liver resection

“…In Hep-3B cell line, short-term isoflurane exposure (<12h) might facilitate cancer cell invasion by enhancing the formation of small ubiquitin-like modifier 2 and 3 (SUMO2/3) conjugates, a kind of stress indicators, while the inhibitor of SUMO2/3 could reverse the response (29). But in primary cultured cells from patients undergoing hepatectomy and general anesthesia, evidence indicated that isoflurane could reduce HCC aggressiveness via down-regulating PI3K/AKT signaling pathway mediated nuclear factor kappaB (NF-kB) activity (30).…”

Cancer-Associated Dysregulation of Sumo Regulators: Proteases and Ligases

“…SENP3 , in combination with ARID1A and CSMD has also been proposed as an effective prognosis marker in HCC, despite molecular heterogeneity detected in HCC patients [ 118 ]. In HCC, it has also been shown that SENP3 overexpression significantly reduces isoflurane-mediated stimulation of sumoylation, resulting in decreased proliferation and invasion of HCC cells [ 117 ].…”