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HCC cells being exposed to isoflurane for 0.5 h, and continued to increase for 48 h, even after the drug had been withdrawn.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 prolifera- tion 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 over- expressed 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 isoflu- rane, 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.