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Protective effects of lidocaine on polycystic ovary syndrome through modulating ovarian granulosa cell physiology via PI3K/AKT/mTOR pathway

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine condition in women that causes adverse reproductive and metabolic effects. PCOS is a heterogeneous disorder and its pathogenesis is affected by different factors. Thus, the criteria for diagnosing PCOS, disease and availability of treatment options vary widely across different countries. Lidocaine has been proven to inhibit the proliferation of a variety of cancer cell types, and can be used alone or in combination with other drugs for the treatment of numerous types of disease. The present study aimed to determine whether lidocaine was able to reduce human ovarian granulosa cell tumor cell line KGN cell proliferation and provide a novel insight into potential therapeutic strategies for PCOS. KGN cells were treated alone with lidocaine at different concentrations, or with lidocaine and insulin-like growth factor-1 (IGF-1; a phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT) signaling pathway agonist) in combination for 48 h. The proliferative ability of KGN cells was detected using an 3-(45)-dimethylthiahiazo (-z-y1)-35-di- phenytetrazoliumromide (MTT) assay, and cell apoptosis was detected using flow cytometry. The expression levels of proteins and mRNAs were measured using western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. The results of the present study revealed that lidocaine significantly suppressed KGN cell proliferation and increased apoptosis. Lidocaine significantly downregulated the protein expression levels of phosphorylated (p)-AKT and p-mTOR, but had no effect on their transcriptional levels. Treatment with IGF-1, could reverse the lidocaine-induced abnormal expression of PI3K/AKT signaling pathway-related proteins. Moreover, treatment with IGF-1 could reverse all the effects of lidocaine on KGN cells. In conclusion, the findings of the present study indicated that lidocaine may inhibit KGN cell proliferation and induce apoptosis by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway. These results revealed the potential inhibitory effect of lidocaine on the proliferation of KGN cells and its underlying mechanism of action, providing a novel insight into potential therapeutic strategies for PCOS.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Abuelezz NZ, Shabana ME, Abdel-Mageed HM, Rashed L, Morcos GNB (2020) Nanocurcumin alleviates insulin resistance and pancreatic deficits in polycystic ovary syndrome rats: Insights on PI3K/AkT/mTOR and TNF-α modulations. Life Sci 256:118003

    CAS  PubMed  Article  Google Scholar 

  • Abuelezz NZ, Shabana E, Rashed L, Morcos G (2021) Nanocurcumin modulates miR-223–3p and NF-κB levels in the pancreas of rat model of polycystic ovary syndrome to attenuate autophagy flare, insulin resistance and improve ß cell mass. J Exp Pharmacol 13:873–888

    PubMed  PubMed Central  Article  Google Scholar 

  • Beaussier M, Delbos A, Maurice-Szamburski A, Ecoffey C, Mercadal L (2018) Perioperative use of intravenous lidocaine. Drugs 78:1229–1246

    CAS  PubMed  Article  Google Scholar 

  • Ben-Shlomo I, Younis JS (2014) Basic research in PCOS: are we reaching new frontiers? Reprod Biomed Online 28:669–683

    CAS  PubMed  Article  Google Scholar 

  • Cai Z, He S, Li T, Zhao L, Zhang K (2020) Plumbagin inhibits proliferation and promotes apoptosis of ovarian granulosa cells in polycystic ovary syndrome by inactivating PI3K/Akt/mTOR pathway. Anim Cells Syst 24:197–204

    CAS  Article  Google Scholar 

  • Chang AY, Oshiro J, Ayers C, Auchus RJ (2016) Influence of race/ethnicity on cardiovascular risk factors in polycystic ovary syndrome, the Dallas Heart Study. Clin Endocrinol 85:92–99

    Article  Google Scholar 

  • Chi XX, Zhang T, Chu XL, Zhen JL, Zhang DJ (2018) The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways. J Vet Med Sci 80:1348–1355

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Copp T, Hersch J, Muscat DM, McCaffery KJ, Doust J, Dokras A, Mol BW, Jansen J (2019) The benefits and harms of receiving a polycystic ovary syndrome diagnosis: a qualitative study of women's experiences. Hum Reprod Open 2019: hoz026.

  • Dietrich JB (1997) Apoptosis and anti-apoptosis genes in the Bcl-2 family. Arch Physiol Biochem 105:125–135

    CAS  PubMed  Article  Google Scholar 

  • Han Q, Zhang W, Meng J, Ma L, Li A (2018) LncRNA-LET inhibits cell viability, migration and EMT while induces apoptosis by up-regulation of TIMP2 in human granulosa-like tumor cell line KGN. Biomed Pharmacother 100:250–256

    CAS  PubMed  Article  Google Scholar 

  • Hanson MA, Gluckman PD (2014) Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 94:1027–1076

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Hong B, He J, Le Q, Bai K, Chen Y, Huang W (2019) Combination formulation of tetrodotoxin and lidocaine as a potential therapy for severe arrhythmias. Mar Drugs 17:685

    CAS  PubMed Central  Article  Google Scholar 

  • Izdebska M, Hałas-Wiśniewska M, Zielińska W, Klimaszewska-Wiśniewska A, Grzanka D, Gagat M (2019) Lidocaine induces protective autophagy in rat C6 glioma cell line. Int J Oncol 54:1099–1111

    CAS  PubMed  Google Scholar 

  • Jin L, Ren L, Lu J, Wen X, Zhuang SY, Geng T, Zhang YZ (2021) CXCL12 and its receptors regulate granulosa cell apoptosis in PCOS rats and human KGN tumor cells. Reproduction 161:145–157

    CAS  PubMed  Article  Google Scholar 

  • Jourdan JP, Bureau R, Rochais C, Dallemagne P (2020) Drug repositioning: a brief overview. J Pharm Pharmacol 72:1145–1151

    CAS  PubMed  Article  Google Scholar 

  • Jurj A, Tomuleasa C, Tat TT, Berindan-Neagoe I, Vesa SV, Ionescu DC (2017) Antiproliferative and apoptotic effects of lidocaine on human hepatocarcinoma cells. A preliminary study. J Gastrointestin Liver Di 26:45–50

    Article  Google Scholar 

  • Kamiya Y, Ohta K, Kaneko Y (2005) Lidocaine-induced apoptosis and necrosis in U937 cells depending on its dosage. Biomed Res 26:231–239

    CAS  PubMed  Article  Google Scholar 

  • Klein JA, Jeske DR (2016) Estimated maximal safe dosages of tumescent lidocaine. Anesth Analg 122:1350–1359

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Li S, Zhu D, Duan H, Tan Q (2013) Genetic investigation into ethnic disparity in polycystic ovarian syndrome. Gynecol Endocrinol 29:878–882

    PubMed  Article  Google Scholar 

  • Li K, Yang J, Han X (2014a) Lidocaine sensitizes the cytotoxicity of cisplatin in breast cancer cells via up-regulation of RARβ2 and RASSF1A demethylation. Int J Mol Sci 15:23519–23536

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Li H, Xu J, Wang X, Yuan G (2014b) Protective effect of ginsenoside Rg1 on lidocaine-induced apoptosis. Mol Med Rep 9:395–400

    CAS  PubMed  Article  Google Scholar 

  • Li L, Mo H, Zhang J, Zhou Y, Peng X, Luo X (2016) The role of heat shock protein 90B1 in patients with polycystic ovary syndrome. PLoS ONE 11:e0152837

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Li T, Mo H, Chen W et al (2017) Role of the PI3K-Akt signaling pathway in the pathogenesis of polycystic ovary syndrome. Reprod Sci 24:646–655

    CAS  PubMed  Article  Google Scholar 

  • Li M, Zhao H, Zhao SG, Wei DM, Zhao YR, Huang T, Muhammad T, Yan L, Gao F, Li L, Lu G, Chan WY, Leung PCK, Dunaif A, Liu HB, Chen ZJ (2019) The HMGA2-IMP2 pathway promotes granulosa cell proliferation in polycystic ovary syndrome. J Clin Endocrinol Metab 104:1049–1059

    PubMed  Article  Google Scholar 

  • Lim S, Smith CA, Costello MF, MacMillan F, Moran L, Ee C (2019) Barriers and facilitators to weight management in overweight and obese women living in Australia with PCOS: a qualitative study. BMC Endocr Disord 19:106

    PubMed  PubMed Central  Article  Google Scholar 

  • Liu Z, Ren YA, Pangas SA, Adams J, Zhou W, Castrillon DH, Wilhelm D, Richards JS (2015) FOXO1/3 and PTEN depletion in granulosa cells promotes ovarian granulosa cell tumor development. Mol Endocrinol 29:1006–1024

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Liu WP, Chen Q, Liu ZD, Weng ZW, Nguyen TN, Feng JM, Zhou SH (2021) Zihuai recipe alleviates cyclophosphamide-induced diminished ovarian reserve via suppressing PI3K/AKT-mediated apoptosis. J Ethnopharmacol 277:113789

    CAS  PubMed  Article  Google Scholar 

  • Liu H, Dilger JP, Lin J (2021) Lidocaine suppresses viability and migration of human breast cancer cells: TRPM7 as a target for some breast cancer cell lines. Cancers 13:234

    CAS  PubMed Central  Article  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCt method. Methods 25:402–408

    CAS  PubMed  Article  Google Scholar 

  • Meier RK (2018) Polycystic ovary syndrome. Nurs Clin North Am 53:407–420

    PubMed  Article  Google Scholar 

  • Nishi Y, Yanase T, Mu Y, Oba K, Ichino I, Saito M, Nomura M, Mukasa C, Okabe T, Goto K, Takayanagi R, Kashimura Y, Haji M, Nawata H (2001) Establishment and characterization of a steroidogenic human granulosa-like tumor cell line, KGN, that expresses functional follicle-stimulating hormone receptor. Endocrinology 142:437–445

    CAS  PubMed  Article  Google Scholar 

  • Rong L, Li Z, Leng X, Li H, Ma Y, Chen Y, Song F (2020) Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway. Biomed Pharmacother 122:109726

    CAS  PubMed  Article  Google Scholar 

  • Rosenfield RL, Ehrmann DA (2016) The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 37:467–520

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ruddenklau A, Campbell RE (2019) Neuroendocrine impairments of polycystic ovary syndrome. Endocrinology 160:2230–2242

    CAS  PubMed  Article  Google Scholar 

  • Slaton RM, Thomas RH, Mbathi JW (2013) Evidence for therapeutic uses of nebulized lidocaine in the treatment of intractable cough and asthma. Ann Pharmacother 47:578–585

    PubMed  Article  CAS  Google Scholar 

  • Song Y, Yu G, Xiang Y, Li Y, Wan L, Tan L (2019) Altered miR-186 and miR-135a contribute to granulosa cell dysfunction by targeting ESR2: A possible role in polycystic ovary syndrome. Mol Cell Endocrinol 494:110478

    CAS  PubMed  Article  Google Scholar 

  • Truesdale K, Jurdi A (2013) Nebulized lidocaine in the treatment of intractable cough. Am J Hosp Palliat Care 30:587–589

    PubMed  Article  Google Scholar 

  • Wang HW, Wang LY, Jiang L, Tian SM, Zhong TD, Fang XM (2016) Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer. J Thorac Dis 8:2748–2757

    PubMed  PubMed Central  Article  Google Scholar 

  • Wang M, Sun J, Xu B, Chrusciel M, Gao J, Bazert M, Stelmaszewska J, Xu Y, Zhang H, Pawelczyk L, Sun F, Tsang SY, Rahman N, Wolczynski S, Li X (2018) Functional characterization of MicroRNA-27a-3p expression in human polycystic ovary syndrome. Endocrinology 159:297–309

    PubMed  Article  CAS  Google Scholar 

  • Wang Z, Liu Q, Lu J, Cao J, Wang XY, Chen Y (2020) Lidocaine promotes autophagy of SH-SY5Y cells through inhibiting PI3K/AKT/mTOR pathway by upregulating miR-145. Toxicol Res 9:467–473

    Article  Google Scholar 

  • Weibel S, Jelting Y, Pace NL, Helf A, Eberhart LH, Hahnenkamp K, Hollmann MW, Poepping DM, Schnabel A, Kranke P (2018) Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev 6:009642

    Google Scholar 

  • Werdehausen R, Braun S, Essmann F, Schulze-Osthoff K, Walczak H, Lipfert P, Stevens MF (2007) Lidocaine induces apoptosis via the mitochondrial pathway independently of death receptor signaling. Anesthesiology 107:136–143

    CAS  PubMed  Article  Google Scholar 

  • Wu C, Jiang F, Wei K, Jiang Z (2018) Exercise activates the PI3K-AKT signal pathway by decreasing the expression of 5α-reductase type 1 in PCOS rats. Sci Rep 8:7982

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Wu G, Xia J, Yang Z, Chen Y, Jiang W, Yin T, Yang J (2020) CircASPH promotes KGN cells proliferation through miR-375/MAP2K6 axis in polycystic ovary syndrome. J Cell Mol Med 00:1–9

    Google Scholar 

  • Xia H, Zhao Y (2020) miR-155 is high-expressed in polycystic ovarian syndrome and promotes cell proliferation and migration through targeting PDCD4 in KGN cells. Artif Cells Nanomed Biotechnol 48:197–205

    CAS  PubMed  Article  Google Scholar 

  • Xu W, Tang M, Wang J, Wang L (2020) Identification of the active constituents and significant pathways of cangfu daotan decoction for the treatment of PCOS based on network pharmacology. Evid Based Complement Alternat Med 2020:4086864

    PubMed  PubMed Central  Google Scholar 

  • Yang X, Zhao L, Li M, Yan L, Zhang S, Mi Z, Ren L, Xu J (2018) Lidocaine enhances the effects of chemotherapeutic drugs against bladder cancer. Sci Rep 8:598

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Yang D, Wang Y, Zheng Y, Dai F, Liu S, Yuan M, Deng Z, Bao A, Cheng Y (2021) Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway. J Ovarian Res 14:48

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ye L, Zhang Y, Chen YJ, Liu Q (2019) Anti-tumor effects of lidocaine on human gastric cancer cells in vitro. Bratisl Lek Listy 120:212–217

    CAS  PubMed  Google Scholar 

  • Zhang L, Hu R, Cheng Y, Wu X, Xi S, Sun Y, Jiang H (2017) Lidocaine inhibits the proliferation of lung cancer by regulating the expression of GOLT1A. Cell Prolif 50:e12364

    PubMed Central  Article  CAS  Google Scholar 

  • Zhang Y, Jia J, Jin W, Cao J, Fu T, Ma D, Zhang Y (2020) Lidocaine inhibits the proliferation and invasion of hepatocellular carcinoma by downregulating USP14 induced PI3K/Akt pathway. Pathol Res Pract 216:152963

    CAS  PubMed  Article  Google Scholar 

  • Zhang N, Liu X, Zhuang L, Liu X, Zhao H, Shan Y, Liu Z, Li F, Wang Y, Fang J (2020) Berberine decreases insulin resistance in a PCOS rats by improving GLUT4: Dual regulation of the PI3K/AKT and MAPK pathways. Regul Toxicol Pharmacol 110:104544

    CAS  PubMed  Article  Google Scholar 

  • Zhao H, Zhou D, Chen Y, Liu D, Chu S, Zhang S (2017) Beneficial effects of Heqi san on rat model of polycystic ovary syndrome through the PI3K/AKT pathway. Daru 25:21

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Zhao L, Ma N, Liu G, Mao N, Chen F, Li J (2021) Lidocaine inhibits hepatocellular carcinoma development by modulating circ_ITCH/miR-421/CPEB3 axis. Dig Dis Sci 66:4384–4397

    CAS  PubMed  Article  Google Scholar 

  • Zheng W, Nagaraju G, Liu Z, Liu K (2012) Functional roles of the phosphatidylinositol 3-kinases (PI3Ks) signaling in the mammalian ovary. Mol Cell Endocrinol 356:24–30

    CAS  PubMed  Article  Google Scholar 

  • Zheng Y, Hou X, Yang S (2019) Lidocaine potentiates SOCS3 to attenuate inflammation in microglia and suppress neuropathic pain. Cell Mol Neurobiol 39:1081–1092

    CAS  PubMed  Article  Google Scholar 

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HX and QH contributed to the study design, data collection, statistical analysis, data interpretation and manuscript preparation. QJ contributed to data collection, statistical analysis and manuscript preparation. HX and QH confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

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Correspondence to Qun Jiang.

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Xiong, H., Hu, Q. & Jiang, Q. Protective effects of lidocaine on polycystic ovary syndrome through modulating ovarian granulosa cell physiology via PI3K/AKT/mTOR pathway. Cytotechnology 74, 283–292 (2022). https://doi.org/10.1007/s10616-022-00528-0

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  • DOI: https://doi.org/10.1007/s10616-022-00528-0

Keywords

  • Polycystic ovary syndrome
  • Lidocaine
  • PI3K/AKT/mTOR
  • Apoptosis
  • Proliferation
  • Granulosa cells