Effect of sufentanil on the viability and apoptosis of cervical cancer cells via the inactivation of PI3K/AKT/mTOR signaling pathway

Objective: To investigate the effect of sufentanil on the viability and apoptosis of cervical cancer HeLa cells, and identify the possible molecular mechanism. Materials and methods: Cervical cancer HeLa cells were treated with different concentrations of sufentanil at 0, 0.5, 5, 50, and 500 nmol/L, respectively. The cell viability of HeLa cells was detected by CCK-8 and EdU assay. Cell apoptosis of HeLa cells was observed by flow cytometry and Hoechst 33258 staining. The relative expression of PI3K, p-PI3K, AKT, p-AKT, mTOR, and p-mTOR was detected by quantitative real-time PCR and Western blotting analysis. PI3K agonist was applied to activate PI3K/AKT signaling, and its effect of on the viability and apoptosis of HeLa cells by 500 nmol/L sufentanil was also determined. Results: Sufentanil had a significant inhibitory effect on the viability of HeLa cells, and the inhibition rates increased with the time and concentration. As the concentration of sufentanil increased, the apoptosis rates of HeLa cells increased. Furthermore, sufentanil markedly inhibited the protein expression of pPI3K, p-AKT, and p-mTOR in a concentration-dependent fashion, but had no affect on the PI3K, AKT, and mTOR mRNA and protein expression. In addition, PI3K agonist significantly increased p-PI3K, p-AKT, and p-mTOR protein expression in HeLa cells, and could partly reverse the effect of 500 nmol/L sufentanil on cell viability and apoptosis. Conclusion: Sufentanil has an inhibitory effect on the viability of cervical cancer HeLa cells by inducing cell apoptosis, the mechanism may be achieved through the inactivation of PI3K/AKT/mTOR signaling pathway.

Sufentanil; Effect; HeLa; PI3K/AKT/mTOR; Mechanism

[1] Tsikouras P, Zervoudis S, Manav B, Tomara E, Iatrakis G, Romanidis C, et al. Cervical cancer: screening, diagnosis and staging. Journal of the Balkan Union of Oncology. 2016; 21: 320–325.

[2] Olusola P, Banerjee HN, Philley JV, Dasgupta S. Human papilloma virus-associated cervical cancer and health disparities. Cells. 2019; 8: 622.

[3] Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Cleveland Clinic Journal of Medicine. 2019; 86: 173–178.

[4] Hu Z, Ma D. The precision prevention and therapy of HPV-related cervical cancer: new concepts and clinical implications. Cancer Medicine. 2018; 7: 5217–5236.

[5] Harper DM, DeMars LR. HPV vaccines - A review of the first decade. Gynecologic Oncology. 2017; 146: 196–204.

[6] Zhu H, Luo H, Zhang W, Shen Z, Hu X, Zhu X. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Design, Development and Therapy. 2017; 10: 1885–1895.

[7] Li J, Chen Q, Deng Z, Chen X, Liu H, Tao Y, et al. KRT17 confers paclitaxel-induced resistance and migration to cervical cancer cells. Life Sciences. 2019; 224: 255–262.

[8] Maciejewski D. Sufentanil in anaesthesiology and intensive therapy. Anaesthesiology Intensive Therapy. 2014; 44: 35–41.

[9] Peng Z, Zhang Y, Guo J, Guo X, Feng Z. Patient-controlled intravenous analgesia for advanced cancer patients with pain: a retrospective series study. Pain Research & Management. 2018; 2018: 7323581.

[10] Blancher M, Maignan M, Clapé C, Quesada JL, Collomb-Muret R, Albasini F, et al. Intranasal sufentanil versus intravenous morphine for acute severe trauma pain: a double-blind randomized non-inferiority study. PLoS Medicine. 2019; 16: e1002849.

[11] Wu QL, Shen T, Ma H, Wang JK. Sufentanil postconditioning protects the myocardium from ischemia-reperfusion via PI3K/Akt-GSK-3β pathway. Journal of Surgical Research. 2012; 178: 563–570.

[12] Liu X, Jing G, Bai J, Yuan H. Effect of sufentanil preconditioning on myocardial P-Akt expression in rats during myocardial ischemia-reperfusion. Nan Fang Yi Ke Da Xue Xue Bao. 2015; 34: 335–340.

[13] Povsic TJ, Kohout TA, Lefkowitz RJ. Beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. Journal of Biological Chemistry. 2004; 278: 51334–51339.

[14] Wu W, Wei N, Jiang C, Cui S, Yuan J. Effects of sufentanil on human gastric cancer cell line SGC-7901 in vitro. Central-European Journal of Immunology. 2015; 39: 299–305.

[15] Vahabi S, Eatemadi A. Effects of anesthetic and analgesic techniques on cancer metastasis. Biomedicine & Pharmacotherapy. 2017; 87: 1–7.

[16] Gao Y, Yu X, Zhang F, Dai J. Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8. Journal of Hepato-BiliaryPancreatic Sciences. 2019; 26: 219–226.

[17] Zhang C, Wang B, Wang X, Sheng X, Cui Y. Sevoflurane inhibits the progression of ovarian cancer through down-regulating stanniocalcin 1 (STC1). Cancer Cell International. 2019; 19: 339.

[18] Zhang L, Hu R, Cheng Y, Wu X, Xi S, Sun Y, et al. Lidocaine inhibits the proliferation of lung cancer by regulating the expression of GOLT1a. Cell Proliferation. 2017; 50: e12364.

[19] Zhang Y, Peng X, Zheng Q. Ropivacaine inhibits the migration of esophageal cancer cells via sodium-channel-independent but prenylation-dependent inhibition of Rac1/JNK/paxillin/FAK. Biochemical and Biophysical Research Communications. 2018; 501: 1074–1079.

[20] Minkowitz HS. A review of sufentanil and the sufentanil sublingual tablet system for acute moderate to severe pain. Pain Management. 2016; 5: 237–250.

[21] Lian Y-H, Fang J, Zhou H-D, Jiang H-F, Xie K-J. Sufentanil preconditioning protects against hepatic ischemia-reperfusion injury by suppressing inflammation. Medical Science Monitor. 2019; 25: 2265–2273.

[22] Zhang Q, Su M. Sufentanil attenuates oxaliplatin cytotoxicity via inhibiting connexin 43-composed gap junction function. Molecular Medicine Reports. 2017; 16: 943–948.

[23] Jiang H, Wang H, Zou W, Hu Y, Chen C, Wang C. Sufentanil impairs autophagic degradation and inhibits cell migration in NCIH460 in vitro. Oncology Letters. 2019; 18: 6829–6835.

[24] Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecologic Oncology. 2015; 137: 173–179.

[25] Polivka J, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacology & Therapeutics. 2014; 142: 164–175.

[26] Wu XL, Wang LK, Yang DD, Qu M, Yang YJ, Guo F, et al. Ef- fects of Glut1 gene silencing on proliferation, differentiation, and apoptosis of colorectal cancer cells by targeting the TGF-β/PI3K-AKT-mTOR signaling pathway. Journal of Cellular Biochemistry. 2018; 119: 2356–2367.

[27] Zhao Y, Sun H, Feng M, Zhao J, Zhao X, Wan Q, et al. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecological Endocrinology. 2018; 34: 428–432.

[28] Ippen FM, Grosch JK, Subramanian M, Kuter BM, Liederer BM, Plise EG, et al. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro-Oncology. 2019; 21: 1401–1411.

[29] Polo ML, Riggio M, May M, Rodríguez MJ, Perrone MC, Stallings-Mann M, et al. Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression. Oncotarget. 2015; 6: 22081–22097.