Skip to main content
Top
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Esketamine | Research

Potential ‘anti-cancer’ effects of esketamine on proliferation, apoptosis, migration and invasion in esophageal squamous carcinoma cells

Authors: Chao Li, Jingpu Shi, Sisi Wei, Huiqun Jia

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Background

Esketamine, an N-methyl-D-aspartate receptor antagonist, is commonly used for anesthesia and analgesia clinically. It was reported to negatively regulate cell proliferation, metastasis and apoptosis in cancer cells, including lung cancer and pancreatic cancer. However, its impact on esophageal squamous cell carcinoma (ESCC) malignance and underlying mechanism remain elusive. This study was aimed to investigate the antitumor effects of esketamine on ESCC in vitro.

Methods

ESCC cell lines (KYSE-30 and KYSE-150) were cultured and treated with different concentrations (0.1, 0.2, 0.4, 0.8, 1, 2 mM) of esketamine. Their proliferation, apoptosis, migration and invasion were assessed with various assays. Furthermore, mass spectrometry-based proteomic analysis and GO/KEGG enrichment analysis were applied to characterize the differentially expressed proteins (DEPs) with or without esketamine treatment. Some key proteins identified from proteomic analysis were further validated with Western blotting and bioinformatics analysis.

Results

Esketamine significantly inhibited the proliferation, migration, invasion and promoted apoptosis of the both types of cell lines in a dose- and time-dependent manner. A total of 321 common DEPs, including 97 upregulated and 224 downregulated proteins, were found with HPLC–MS analyses. GO/KEGG enrichment analysis suggested that esketamine affected cell population proliferation, GTPase activity and Apelin signaling pathway. The ERCC6L, AHR and KIF2C protein expression was significantly downregulated in these ESCC cells treated with esketamine compared to the controls and their changes were associated with the suppressive effects of esketamine on ESCC through bioinformatics analysis.

Conclusions

Our work demonstrated that esketamine has potential anti-ESCC properties in vitro but subjected to further in vivo and clinical study.
Appendix
Available only for authorised users
Literature
1.
go back to reference Morgan E, Soerjomataram I, Rumgay H, Coleman HG, Thrift AP, Vignat J, Laversanne M, Ferlay J, Arnold M. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022;163:649-658.e642.CrossRefPubMed Morgan E, Soerjomataram I, Rumgay H, Coleman HG, Thrift AP, Vignat J, Laversanne M, Ferlay J, Arnold M. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022;163:649-658.e642.CrossRefPubMed
2.
go back to reference Li J, Xu J, Zheng Y, Gao Y, He S, Li H, Zou K, Li N, Tian J, Chen W, He J. Esophageal cancer: epidemiology, risk factors and screening. Chin J Cancer Res. 2021;33:535–47.CrossRefPubMedPubMedCentral Li J, Xu J, Zheng Y, Gao Y, He S, Li H, Zou K, Li N, Tian J, Chen W, He J. Esophageal cancer: epidemiology, risk factors and screening. Chin J Cancer Res. 2021;33:535–47.CrossRefPubMedPubMedCentral
4.
go back to reference Alam A, Rampes S, Patel S, Hana Z, Ma D. Anesthetics or anesthetic techniques and cancer surgical outcomes: a possible link. Korean J Anesthesiol. 2021;74:191–203.CrossRefPubMedPubMedCentral Alam A, Rampes S, Patel S, Hana Z, Ma D. Anesthetics or anesthetic techniques and cancer surgical outcomes: a possible link. Korean J Anesthesiol. 2021;74:191–203.CrossRefPubMedPubMedCentral
5.
go back to reference Ishikawa M, Iwasaki M, Sakamoto A, Ma D. Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation. BMC Anesthesiol. 2021;21:71.CrossRefPubMedPubMedCentral Ishikawa M, Iwasaki M, Sakamoto A, Ma D. Anesthetics may modulate cancer surgical outcome: a possible role of miRNAs regulation. BMC Anesthesiol. 2021;21:71.CrossRefPubMedPubMedCentral
7.
go back to reference Santoni A, Santoni M, Arcuri E. Chronic cancer pain: opioids within tumor microenvironment affect neuroinflammation, tumor and pain evolution. Cancers (Basel). 2022;14:2253.CrossRefPubMed Santoni A, Santoni M, Arcuri E. Chronic cancer pain: opioids within tumor microenvironment affect neuroinflammation, tumor and pain evolution. Cancers (Basel). 2022;14:2253.CrossRefPubMed
8.
go back to reference Lu H, Zhang H, Weng ML, Zhang J, Jiang N, Cata JP, Ma D, Chen WK, Miao CH. Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer. J Cell Physiol. 2021;236:4445–54.CrossRefPubMed Lu H, Zhang H, Weng ML, Zhang J, Jiang N, Cata JP, Ma D, Chen WK, Miao CH. Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer. J Cell Physiol. 2021;236:4445–54.CrossRefPubMed
9.
go back to reference Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33:633–8.CrossRefPubMed Barrett W, Buxhoeveden M, Dhillon S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33:633–8.CrossRefPubMed
11.
go back to reference Culp C, Kim HK, Abdi S. Ketamine use for cancer and chronic pain management. Front Pharmacol. 2020;11: 599721.CrossRefPubMed Culp C, Kim HK, Abdi S. Ketamine use for cancer and chronic pain management. Front Pharmacol. 2020;11: 599721.CrossRefPubMed
12.
go back to reference Ionescu DF, Fu DJ, Qiu X, Lane R, Lim P, Kasper S, Hough D, Drevets WC, Manji H, Canuso CM. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24:22–31.CrossRefPubMed Ionescu DF, Fu DJ, Qiu X, Lane R, Lim P, Kasper S, Hough D, Drevets WC, Manji H, Canuso CM. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24:22–31.CrossRefPubMed
13.
go back to reference Hirota K, Lambert DG. Ketamine; history and role in anesthetic pharmacology. Neuropharmacology. 2022;216: 109171.CrossRefPubMed Hirota K, Lambert DG. Ketamine; history and role in anesthetic pharmacology. Neuropharmacology. 2022;216: 109171.CrossRefPubMed
14.
go back to reference Duan W, Hu J, Liu Y. Ketamine inhibits colorectal cancer cells malignant potential via blockage of NMDA receptor. Exp Mol Pathol. 2019;107:171–8.CrossRefPubMed Duan W, Hu J, Liu Y. Ketamine inhibits colorectal cancer cells malignant potential via blockage of NMDA receptor. Exp Mol Pathol. 2019;107:171–8.CrossRefPubMed
15.
go back to reference Du S, Sung YS, Wey M, Wang Y, Alatrash N, Berthod A, MacDonnell FM, Armstrong DW. Roles of N-methyl-d-aspartate receptors and d-amino acids in cancer cell viability. Mol Biol Rep. 2020;47:6749–58.CrossRefPubMed Du S, Sung YS, Wey M, Wang Y, Alatrash N, Berthod A, MacDonnell FM, Armstrong DW. Roles of N-methyl-d-aspartate receptors and d-amino acids in cancer cell viability. Mol Biol Rep. 2020;47:6749–58.CrossRefPubMed
16.
go back to reference Saito J, Zao H, Wu L, Iwasaki M, Sun Q, Hu C, Ishikawa M, Hirota K, Ma D. “Anti-cancer” effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells. Eur J Pharmacol. 2023;945: 175580.CrossRefPubMed Saito J, Zao H, Wu L, Iwasaki M, Sun Q, Hu C, Ishikawa M, Hirota K, Ma D. “Anti-cancer” effect of ketamine in comparison with MK801 on neuroglioma and lung cancer cells. Eur J Pharmacol. 2023;945: 175580.CrossRefPubMed
17.
go back to reference Malsy M, Gebhardt K, Gruber M, Wiese C, Graf B, Bundscherer A. Effects of ketamine, s-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells. BMC Anesthesiol. 2015;15:111.CrossRefPubMedPubMedCentral Malsy M, Gebhardt K, Gruber M, Wiese C, Graf B, Bundscherer A. Effects of ketamine, s-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells. BMC Anesthesiol. 2015;15:111.CrossRefPubMedPubMedCentral
18.
go back to reference Li T, Yang J, Yang B, Zhao G, Lin H, Liu Q, Wang L, Wan Y, Jiang H. Ketamine inhibits ovarian cancer cell growth by regulating the lncRNA-PVT1/EZH2/p57 axis. Front Genet. 2020;11: 597467.CrossRefPubMed Li T, Yang J, Yang B, Zhao G, Lin H, Liu Q, Wang L, Wan Y, Jiang H. Ketamine inhibits ovarian cancer cell growth by regulating the lncRNA-PVT1/EZH2/p57 axis. Front Genet. 2020;11: 597467.CrossRefPubMed
19.
go back to reference Gu L, Sang Y, Nan X, Zheng Y, Liu F, Meng L, Sang M, Shan B. circCYP24A1 facilitates esophageal squamous cell carcinoma progression through binding PKM2 to regulate NF-κB-induced CCL5 secretion. Mol Cancer. 2022;21:217.CrossRefPubMedPubMedCentral Gu L, Sang Y, Nan X, Zheng Y, Liu F, Meng L, Sang M, Shan B. circCYP24A1 facilitates esophageal squamous cell carcinoma progression through binding PKM2 to regulate NF-κB-induced CCL5 secretion. Mol Cancer. 2022;21:217.CrossRefPubMedPubMedCentral
20.
go back to reference Shen J, Han L, Xue Y, Li C, Jia H, Zhu K. Ropivacaine inhibits lung cancer cell malignancy through downregulation of cellular signaling including HIF-1α in vitro. Front Pharmacol. 2021;12: 806954.CrossRefPubMed Shen J, Han L, Xue Y, Li C, Jia H, Zhu K. Ropivacaine inhibits lung cancer cell malignancy through downregulation of cellular signaling including HIF-1α in vitro. Front Pharmacol. 2021;12: 806954.CrossRefPubMed
21.
go back to reference Li H, Liu W, Zhang X, Wu F, Sun D, Wang Z. Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis. Biochem Biophys Res Commun. 2021;585:111–6.CrossRefPubMed Li H, Liu W, Zhang X, Wu F, Sun D, Wang Z. Ketamine suppresses proliferation and induces ferroptosis and apoptosis of breast cancer cells by targeting KAT5/GPX4 axis. Biochem Biophys Res Commun. 2021;585:111–6.CrossRefPubMed
22.
go back to reference Cheng Y, Wang G, Zhao L, Dai S, Han J, Hu X, Zhou C, Wang F, Ma H, Li B, Meng Z. Periplocymarin induced colorectal cancer cells apoptosis via impairing PI3K/AKT pathway. Front Oncol. 2021;11: 753598.CrossRefPubMedPubMedCentral Cheng Y, Wang G, Zhao L, Dai S, Han J, Hu X, Zhou C, Wang F, Ma H, Li B, Meng Z. Periplocymarin induced colorectal cancer cells apoptosis via impairing PI3K/AKT pathway. Front Oncol. 2021;11: 753598.CrossRefPubMedPubMedCentral
23.
go back to reference Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98-w102.CrossRefPubMedPubMedCentral Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98-w102.CrossRefPubMedPubMedCentral
24.
go back to reference Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49:D605-d612.CrossRefPubMed Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, Doncheva NT, Legeay M, Fang T, Bork P, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49:D605-d612.CrossRefPubMed
25.
go back to reference Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.CrossRefPubMed Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.CrossRefPubMed
26.
go back to reference Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.CrossRefPubMed Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39:782–95.CrossRefPubMed
27.
go back to reference Chen H, Wang H, Yu X, Zhou S, Zhang Y, Wang Z, Huang S, Wang Z. ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway. BMC Cancer. 2020;20:853.CrossRefPubMedPubMedCentral Chen H, Wang H, Yu X, Zhou S, Zhang Y, Wang Z, Huang S, Wang Z. ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway. BMC Cancer. 2020;20:853.CrossRefPubMedPubMedCentral
28.
go back to reference Liu S, Ye Z, Xue VW, Sun Q, Li H, Lu D. KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer. BMC Cancer. 2023;23:307.CrossRefPubMedPubMedCentral Liu S, Ye Z, Xue VW, Sun Q, Li H, Lu D. KIF2C is a prognostic biomarker associated with immune cell infiltration in breast cancer. BMC Cancer. 2023;23:307.CrossRefPubMedPubMedCentral
29.
go back to reference Wei S, Dai M, Zhang C, Teng K, Wang F, Li H, Sun W, Feng Z, Kang T, Guan X, et al. KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein Cell. 2021;12:788–809.CrossRefPubMed Wei S, Dai M, Zhang C, Teng K, Wang F, Li H, Sun W, Feng Z, Kang T, Guan X, et al. KIF2C: a novel link between Wnt/β-catenin and mTORC1 signaling in the pathogenesis of hepatocellular carcinoma. Protein Cell. 2021;12:788–809.CrossRefPubMed
30.
go back to reference Leclerc D, Staats Pires AC, Guillemin GJ, Gilot D. Detrimental activation of AhR pathway in cancer: an overview of therapeutic strategies. Curr Opin Immunol. 2021;70:15–26.CrossRefPubMed Leclerc D, Staats Pires AC, Guillemin GJ, Gilot D. Detrimental activation of AhR pathway in cancer: an overview of therapeutic strategies. Curr Opin Immunol. 2021;70:15–26.CrossRefPubMed
31.
go back to reference Zhang B, Peng H, Zhou M, Bao L, Wang C, Cai F, Zhang H, Wang JE, Niu Y, Chen Y, et al. Targeting BCAT1 combined with α-Ketoglutarate triggers metabolic synthetic lethality in glioblastoma. Cancer Res. 2022;82:2388–402.CrossRefPubMedPubMedCentral Zhang B, Peng H, Zhou M, Bao L, Wang C, Cai F, Zhang H, Wang JE, Niu Y, Chen Y, et al. Targeting BCAT1 combined with α-Ketoglutarate triggers metabolic synthetic lethality in glioblastoma. Cancer Res. 2022;82:2388–402.CrossRefPubMedPubMedCentral
32.
go back to reference Liu R, Liu R, Guo Z, Ren J, Huang J, Luo Q, Tan Q. shRNA-mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8. Cell Death Dis. 2022;13:685.CrossRefPubMedPubMedCentral Liu R, Liu R, Guo Z, Ren J, Huang J, Luo Q, Tan Q. shRNA-mediated knockdown of KNTC1 inhibits non-small-cell lung cancer through regulating PSMB8. Cell Death Dis. 2022;13:685.CrossRefPubMedPubMedCentral
33.
go back to reference Muller J, Pentyala S, Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol. 2016;6:185–92.CrossRefPubMedPubMedCentral Muller J, Pentyala S, Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol. 2016;6:185–92.CrossRefPubMedPubMedCentral
34.
go back to reference Fernandes M, Schelotto M, Doldi PM, Milani G, Ariza Manzano AA, Perera Valdivia D, Winter Matos AM, Hamdy Abdelrahim Y, Hamad Bek SA, Benitez BK, et al. IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain. F1000Res. 2021;10:42.CrossRefPubMedPubMedCentral Fernandes M, Schelotto M, Doldi PM, Milani G, Ariza Manzano AA, Perera Valdivia D, Winter Matos AM, Hamdy Abdelrahim Y, Hamad Bek SA, Benitez BK, et al. IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain. F1000Res. 2021;10:42.CrossRefPubMedPubMedCentral
35.
go back to reference Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2018;75:139–48.CrossRef Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, Thase ME, Winokur A, Van Nueten L, Manji H, Drevets WC. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2018;75:139–48.CrossRef
36.
go back to reference Li L, Jiang D, Zhang Q, Liu H, Xu F, Guo C, Qin Z, Wang H, Feng J, Liu Y, et al. Integrative proteogenomic characterization of early esophageal cancer. Nat Commun. 2023;14:1666.CrossRefPubMedPubMedCentral Li L, Jiang D, Zhang Q, Liu H, Xu F, Guo C, Qin Z, Wang H, Feng J, Liu Y, et al. Integrative proteogenomic characterization of early esophageal cancer. Nat Commun. 2023;14:1666.CrossRefPubMedPubMedCentral
37.
go back to reference Wang Y, Wang G, Liu X, Yun D, Cui Q, Wu X, Lu W, Yang X, Zhang M. Inhibition of APLN suppresses cell proliferation and migration and promotes cell apoptosis in esophageal cancer cells in vitro, through activating PI3K/mTOR signaling pathway. Eur J Histochem. 2022;66:3336.CrossRefPubMedPubMedCentral Wang Y, Wang G, Liu X, Yun D, Cui Q, Wu X, Lu W, Yang X, Zhang M. Inhibition of APLN suppresses cell proliferation and migration and promotes cell apoptosis in esophageal cancer cells in vitro, through activating PI3K/mTOR signaling pathway. Eur J Histochem. 2022;66:3336.CrossRefPubMedPubMedCentral
39.
go back to reference Hou G, Lu Z, Bi Y, Deng J, Yang X. ERCC6L is a biomarker and therapeutic target for non-small cell lung adenocarcinoma. Med Oncol. 2022;39:51.CrossRefPubMed Hou G, Lu Z, Bi Y, Deng J, Yang X. ERCC6L is a biomarker and therapeutic target for non-small cell lung adenocarcinoma. Med Oncol. 2022;39:51.CrossRefPubMed
40.
go back to reference Moon HH, Kreis NN, Friemel A, Roth S, Schulte D, Solbach C, Louwen F, Yuan J, Ritter A. Mitotic centromere-associated kinesin (MCAK/KIF2C) regulates cell migration and invasion by modulating microtubule dynamics and focal adhesion turnover. Cancers (Basel). 2021;13:5673.CrossRefPubMed Moon HH, Kreis NN, Friemel A, Roth S, Schulte D, Solbach C, Louwen F, Yuan J, Ritter A. Mitotic centromere-associated kinesin (MCAK/KIF2C) regulates cell migration and invasion by modulating microtubule dynamics and focal adhesion turnover. Cancers (Basel). 2021;13:5673.CrossRefPubMed
Metadata
Title
Potential ‘anti-cancer’ effects of esketamine on proliferation, apoptosis, migration and invasion in esophageal squamous carcinoma cells
Authors
Chao Li
Jingpu Shi
Sisi Wei
Huiqun Jia
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01511-x

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue