Cucurbitacin E Glucoside as an Apoptosis Inducer in Melanoma Cancer Cells by Modulating AMPK/PGK1/PKM2 Pathway


Cite item

Full Text

Abstract

Background:Cucurbitacin E glucoside (CEG), a prominent constituent of Cucurbitaceae plants, exhibits notable effects on cancer cell behavior, including inhibition of invasion and migration, achieved through mechanisms such as apoptosis induction, autophagy, cell cycle arrest, and disruption of the actin cytoskeleton.

Objective:Melanoma, the fastest-growing malignancy among young individuals in the United States and the predominant cancer among young adults aged 25 to 29, poses a significant health threat.

Methods:The study estimated the IC50 of CEG against the A375 cell line and assessed cell viability, apoptosis, and necrosis upon CEG treatment. Additionally, IC50 values of CEG against Phosphoglycerate kinase1 (PGK1) and Pyruvate Kinase M2 (PKM2) were determined at various levels of concentrations. The impact of CEG on intracellular glutathione (GSH) levels and the activity of key enzymes (GR, SOD, GPx, CAT), as well as markers of apoptosis (P53), and cell cycle regulation (cyclin D1, cyclin E2, cdk2, cdk4), were estimated. Finally, the level of AMP-activated protein kinase (AMPK), PGK1, and PKM2 gene expression levels in A375 cells were also evaluated.

Results:The IC50 value of CEG against A375 cells was determined to be 41.87 ± 2.47 μg/mL. A375 cells treated with CEG showed a significant increase in the G0/G1 phase and a decrease in the S and G2/M phases, indicating cell cycle arrest and reduced proliferation. Additionally, there was an increase in the sub-G1 peak, suggesting enhanced apoptosis. Additionally, the pharmacological analysis revealed potent inhibitory activity of CEG against both PGK1 and PKM2 gene expression, with IC50 values 27.89, 11.70, 7.43 and 2.74 μg/mL after incubation periods interval of 30, 60, 90 and 120 minutes, respectively. In In-Silico study, computational simulations showed a strong binding affinity of CEG towards AMPK, PGK1, and PKM2 activities, with estimated binding energy (ΔG) values of -6.5, -7.9, and -8.3 kcal/mol, respectively. Furthermore, incubation of A375 cells with CEG (at concentrations of 20.9, 41.87, and 83.74 μg/mL) led to a significant decrease in GSH levels and the activity of GR, SOD, GPx, CAT, cyclin D1, cyclin E2, cdk2, and cdk4. Notably, CEG treatment upregulated AMPK levels while downregulating PGK1 and PKM2 gene expression significantly.

Conclusion:CEG induces apoptosis in melanoma cancer cells (A375) through various mechanisms, including enhanced production of p53 and MDA, inhibition of key enzymes (GR, SOD, GPx, CAT) involved in oxidative stress defense and production of cell cycle regulating enzymes (cyclin D1, cyclin E2, cdk2, cdk4, and upregulation of AMPK and downregulation PGK1, and PKM2 in A375 tumor cells pathways. The downregulation of PKM2 in CEG-treated A375 cells inhibits ATP generation via aerobic glycolysis, a metabolic preference of cancer cells.

Aim:This study aims to elucidate the apoptotic mechanism of CEG against the melanoma cancer cell line (A375).

About the authors

Mohammed Hussein

Department of Biotechnology, Faculty of Applied Health Science, October 6 University

Author for correspondence.
Email: info@benthamscience.net

Aya Sallam

Department of Biotechnology, Faculty of Applied Health Science,, October 6 University

Email: info@benthamscience.net

Shaza Mohamed

Department of Biotechnology, Faculty of Applied Health Science,, October 6 University

Email: info@benthamscience.net

Amera Abdel-Rady

Department of Biotechnology, Faculty of Applied Health Science, October 6 University

Email: info@benthamscience.net

Adam Maghrabe

Department of Biotechnology, Faculty of Applied Health Science,, October 6 University

Email: info@benthamscience.net

Abdelrahman Soltan

Department of Biotechnology, Faculty of Applied Health Science, October 6 University

Email: info@benthamscience.net

Hanan Abdelhamid

Department of Biotechnology, Faculty of Applied Health Science, October 6 University

Email: info@benthamscience.net

Gaber Eldesoky

Department of Chemistry, College of Science, King Saud University

Email: info@benthamscience.net

Seikh Alam

Department of Chemistry, Aliah University, New Town

Email: info@benthamscience.net

Mohammad Islam

Department of Chemistry, College of Science, King Saud University

Email: info@benthamscience.net

References

  1. Hayat, M.J.; Howlader, N.; Reichman, M.E.; Edwards, B.K. Cancer statistics, trends, and multiple primary cancer analyses from the surveillance, epidemiology, and end results (SEER) program. Oncologist, 2007, 12(1), 20-37. doi: 10.1634/theoncologist.12-1-20 PMID: 17227898
  2. El Gizawy, H.A.E.H.; Hussein, M.A.; Abdel-Sattar, E. Biological activities, isolated compounds and HPLC profile of Verbascum nubicum. Pharm. Biol., 2019, 57(1), 485-497. doi: 10.1080/13880209.2019.1643378 PMID: 31401911
  3. Hussein, M.A. Anti-obesity, antiatherogenic, anti-diabetic and antioxidant activities of J. montana ethanolic formulation in obese diabetic rats fed high-fat diet. Free Radic. Antioxid., 2011, 1(1), 49-60. doi: 10.5530/ax.2011.1.9
  4. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 2009, 324(5930), 1029-1033. doi: 10.1126/science.1160809 PMID: 19460998
  5. Stein, E.M.; DiNardo, C.D.; Pollyea, D.A.; Fathi, A.T.; Roboz, G.J.; Altman, J.K.; Stone, R.M.; DeAngelo, D.J.; Levine, R.L.; Flinn, I.W.; Kantarjian, H.M.; Collins, R.; Patel, M.R.; Frankel, A.E.; Stein, A.; Sekeres, M.A.; Swords, R.T.; Medeiros, B.C.; Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R.D.; Yen, K.E.; Agresta, S.; de Botton, S.; Tallman, M.S. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood, 2017, 130(6), 722-731. doi: 10.1182/blood-2017-04-779405 PMID: 28588020
  6. Hussein, M.A.; Ismail, N.E.M.; Mohamed, A.H.; Borik, R.M.; Ali, A.A.; Mosaad, Y.O. Plasma phospholipids: A promising simple biochemical parameter to evaluate COVID-19 infection severity. Bioinform. Biol. Insights, 2021, 15, 11779322211055891. doi: 10.1177/11779322211055891 PMID: 34840499
  7. Shehata, M.R.; Mohamed, M.M.A.; Shoukry, M.M.; Hussein, M.A.; Hussein, F.M. Synthesis, characterization, equilibria and biological activity of dimethyltin(IV) complex with 1,4-piperazine. J. Coord. Chem., 2015, 68(6), 1101-1114. doi: 10.1080/00958972.2015.1007962
  8. El-gizawy, H.A.E.; Hussein, M.A. Isolation, structure elucidation of ferulic and coumaric acids from Fortunella japonica swingle leaves and their structure antioxidant activity relationship. Free Radic. Antioxid., 2016, 7(1), 23-30. doi: 10.5530/fra.2017.1.4
  9. Zheng, Q.; Lin, Z.; Xu, J.; Lu, Y.; Meng, Q.; Wang, C.; Yang, Y.; Xin, X.; Li, X.; Pu, H.; Gui, X.; Li, T.; Xiong, W.; Lu, D. Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN. Cell Death Dis., 2018, 9(3), 253. doi: 10.1038/s41419-018-0305-7 PMID: 29449541
  10. Benesch, C.; Schneider, C.; Voelker, H-U.; Kapp, M.; Caffier, H.; Krockenberger, M.; Dietl, J.; Kammerer, U.; Schmidt, M. The clinicopathological and prognostic relevance of pyruvate kinase M2 and pAkt expression in breast cancer. Anticancer Res., 2010, 30(5), 1689-1694. PMID: 20592362
  11. Tang, S.J.; Ho, M.Y.; Cho, H.C.; Lin, Y.C.; Sun, G.H.; Chi, K.H.; Wang, Y.S.; Jhou, R.S.; Yang, W.; Sun, K.H. Phosphoglycerate kinase 1‐overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti‐tumor immunity in vivo. Int. J. Cancer, 2008, 123(12), 2840-2848. doi: 10.1002/ijc.23888 PMID: 18814280
  12. Mohammed Abdalla, H., Jr; Soad Mohamed, A.G. In vivo hepato-protective properties of purslane extracts on paracetamol-induced liver damage. Malays. J. Nutr., 2010, 16(1), 161-170. PMID: 22691863
  13. Mohamad, E.A.; Mohamed, Z.N.; Hussein, M.A.; Elneklawi, M.S. GANE can improve lung fibrosis by reducing inflammation via promoting p38MAPK/TGF-β1/NF-κB signaling pathway downregulation. ACS Omega, 2022, 7(3), 3109-3120. doi: 10.1021/acsomega.1c06591 PMID: 35097306
  14. El Gizawy, H.A.; Abo-Salem, H.M.; Ali, A.A.; Hussein, M.A. Phenolic profiling and therapeutic potential of certain isolated compounds from parkia roxburghii against AChE activity as well as GABAA α5, GSK-3β, and p38α MAP-kinase genes. ACS Omega, 2021, 6(31), 20492-20511. doi: 10.1021/acsomega.1c02340 PMID: 34395996
  15. Gobba, N.A.E.K.; Hussein Ali, A.; El Sharawy, D.E.; Hussein, M.A. The potential hazardous effect of exposure to iron dust in Egyptian smoking and nonsmoking welders. Arch. Environ. Occup. Health, 2018, 73(3), 189-202. doi: 10.1080/19338244.2017.1314930 PMID: 28375782
  16. Wang, J.; Wang, J.; Dai, J.; Jung, Y.; Wei, C.L.; Wang, Y.; Havens, A.M.; Hogg, P.J.; Keller, E.T.; Pienta, K.J.; Nor, J.E.; Wang, C.Y.; Taichman, R.S. A glycolytic mechanism regulating an angiogenic switch in prostate cancer. Cancer Res., 2007, 67(1), 149-159. doi: 10.1158/0008-5472.CAN-06-2971 PMID: 17210694
  17. Faubert, B.; Boily, G.; Izreig, S.; Griss, T.; Samborska, B.; Dong, Z.; Dupuy, F.; Chambers, C.; Fuerth, B.J.; Viollet, B.; Mamer, O.A.; Avizonis, D.; DeBerardinis, R.J.; Siegel, P.M.; Jones, R.G. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab., 2013, 17(1), 113-124. doi: 10.1016/j.cmet.2012.12.001 PMID: 23274086
  18. Zhou, Y.; Farooqi, A.A.; Xu, B. Comprehensive review on signaling pathways of dietary saponins in cancer cells suppression. Crit. Rev. Food Sci. Nutr., 2023, 63(20), 4325-4350. doi: 10.1080/10408398.2021.2000933 PMID: 34751072
  19. Chen, Y.F.; Yang, C.H.; Chang, M.S.; Ciou, Y.P.; Huang, Y.C. Foam properties and detergent abilities of the saponins from Camellia oleifera. Int. J. Mol. Sci., 2010, 11(11), 4417-4425. doi: 10.3390/ijms11114417 PMID: 21151446
  20. Barbosa, A.D.P. An overview on the biological and pharmacological activities of saponins. Int. J. Pharm. Pharm. Sci., 2014, 6, 47-50.
  21. Man, S.; Gao, W.; Zhang, Y.; Huang, L.; Liu, C. Chemical study and medical application of saponins as anti-cancer agents. Fitoterapia, 2010, 81(7), 703-714. doi: 10.1016/j.fitote.2010.06.004 PMID: 20550961
  22. Ramalhete, C.; Gonçalves, B.M.F.; Barbosa, F.; Duarte, N.; Ferreira, M.J.U. Momordica balsamina: Phytochemistry and pharmacological potential of a gifted species. Phytochem. Rev., 2022, 21(2), 617-646. doi: 10.1007/s11101-022-09802-7 PMID: 35153639
  23. Borik, R.M.; Hussein, M.A. Synthesis, molecular docking, biological potentials and structure activity relationship of new quinazoline and quinazoline-4-one derivatives. Asian J. Chem., 2021, 33(2), 423-438. doi: 10.14233/ajchem.2021.23036
  24. Boshra, S.; Hussein, M. Cranberry extract as a supplemented food in treatment of oxidative stress and breast cancer induced by N-Methyl-N-Nitrosourea in female virgin rats. Int. J. Phytomed., 2016, 8, 217-227.
  25. Hussein, M.A.; Borik, R.M. A novel quinazoline-4-one derivatives as a promising cytokine inhibitors: Synthesis, molecular docking, and structure-activity relationship. Curr. Pharm. Biotechnol., 2022, 23(9), 1179-1203. doi: 10.2174/1389201022666210601170650 PMID: 34077343
  26. Hansen, M.B.; Nielsen, S.E.; Berg, K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Methods, 1989, 119(2), 203-210. doi: 10.1016/0022-1759(89)90397-9 PMID: 2470825
  27. Crowley, L.C.; Marfell, B.J.; Scott, A.P.; Waterhouse, N.J. Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. Cold Spring Harb. Protoc., 2016, 2016(11), pdb.prot087288. doi: 10.1101/pdb.prot087288 PMID: 27803250
  28. Chen, X.; Zhao, C.; Li, X.; Wang, T.; Li, Y.; Cao, C.; Ding, Y.; Dong, M.; Finci, L.; Wang, J.; Li, X.; Liu, L. Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nat. Chem. Biol., 2015, 11(1), 19-25. doi: 10.1038/nchembio.1657 PMID: 25383758
  29. Vander Heiden, M.G.; Christofk, H.R.; Schuman, E.; Subtelny, A.O.; Sharfi, H.; Harlow, E.E.; Xian, J.; Cantley, L.C. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol., 2010, 79(8), 1118-1124. doi: 10.1016/j.bcp.2009.12.003 PMID: 20005212
  30. Akerboom, T.P.M.; Sies, H. Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol., 1981, 77, 373-382. doi: 10.1016/S0076-6879(81)77050-2 PMID: 7329314
  31. Tampa, M.; Nicolae, I.; Ene, C.D.; Sarbu, I.; Matei, C.; Georgescu, S.R. Vitamin C and thiobarbituric acid reactive substances (TBARS) in Psoriasis vulgaris related to psoriasis area severity index (PASI). Revista de Chimie, 2017, 68(1), 43-47. doi: 10.37358/RC.17.1.5385
  32. Nishikimi, M.; Appaji Rao, N.; Yagi, K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem. Biophys. Res. Commun., 1972, 46(2), 849-854. doi: 10.1016/S0006-291X(72)80218-3 PMID: 4400444
  33. Aebi, H. Catalase in vitro; Methods in EnzymologyElsevier, 1984, pp. 121-126.
  34. Maiorino, F.M.; Brigelius-Flohé, R.; Aumann, K.; Roveri, A.; Schomburg, D.; Flohé, L. Diversity of glutathione peroxidases; Methods in Enzymology, Elsevier, 1995, pp. 38-53.
  35. Dym, O.; Eisenberg, D. Sequence‐structure analysis of FAD‐containing proteins. Protein Sci., 2001, 10(9), 1712-1728. doi: 10.1110/ps.12801 PMID: 11514662
  36. Xiong, G.; Wu, Z.; Yi, J.; Fu, L.; Yang, Z.; Hsieh, C.; Yin, M.; Zeng, X.; Wu, C.; Lu, A.; Chen, X.; Hou, T.; Cao, D. ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res., 2021, 49(W1), W5-W14. doi: 10.1093/nar/gkab255 PMID: 33893803
  37. Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17. doi: 10.1186/1758-2946-4-17 PMID: 22889332
  38. Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791. doi: 10.1002/jcc.21256 PMID: 19399780
  39. Jiménez, J.; Doerr, S.; Martínez-Rosell, G.; Rose, A.S.; De Fabritiis, G. DeepSite: Protein-binding site predictor using 3D-convolutional neural networks. Bioinformatics, 2017, 33(19), 3036-3042. doi: 10.1093/bioinformatics/btx350 PMID: 28575181
  40. Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461. doi: 10.1002/jcc.21334 PMID: 19499576
  41. Systèmes, D.B. Discovery Studio Modeling Environment, Release 2019; Dassault Systèmes, 2019.
  42. Gorbalenya, A.E.; Baker, S.C.; Baric, R.S.; de Groot, R.J.; Drosten, C.; Gulyaeva, A.A.; Haagmans, B.L.; Lauber, C.; Leontovich, A.M.; Neuman, B.W.; Penzar, D.; Perlman, S.; Poon, L.L.M.; Samborskiy, D.V.; Sidorov, I.A.; Sola, I.; Ziebuhr, J. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol., 2020, 5(4), 536-544. doi: 10.1038/s41564-020-0695-z PMID: 32123347
  43. Wu, P.L.; Lin, F.W.; Wu, T.S.; Kuoh, C.S.; Lee, K.H.; Lee, S.J. Cytotoxic and anti-HIV principles from the rhizomes of Begonia nantoensis. Chem. Pharm. Bull., 2004, 52(3), 345-349. doi: 10.1248/cpb.52.345 PMID: 14993759
  44. Kong, Y.; Chen, J.; Zhou, Z.; Xia, H.; Qiu, M.H.; Chen, C. Cucurbitacin E induces cell cycle G2/M phase arrest and apoptosis in triple negative breast cancer. PLoS One, 2014, 9(7), e103760. doi: 10.1371/journal.pone.0103760 PMID: 25072848
  45. He, X.; Gao, Q.; Qiang, Y.; Guo, W.; Ma, Y. Cucurbitacin E induces apoptosis of human prostate cancer cells via cofilin-1 and mTORC1. Oncol. Lett., 2017, 13(6), 4905-4910. doi: 10.3892/ol.2017.6086 PMID: 28599494
  46. Tannin-Spitz, T.; Grossman, S.; Dovrat, S.; Gottlieb, H.E.; Bergman, M. Growth inhibitory activity of cucurbitacin glucosides isolated from Citrullus colocynthis on human breast cancer cells. Biochem. Pharmacol., 2007, 73(1), 56-67. doi: 10.1016/j.bcp.2006.09.012 PMID: 17049494
  47. Mostafa, M.M.; Amin, M.M.; Zakaria, M.Y.; Hussein, M.A.; Shamaa, M.M.; Abd El-Halim, S.M. Chitosan surface-modified PLGA nanoparticles loaded with cranberry powder extract as a potential oral delivery platform for targeting colon cancer cells. Pharmaceutics, 2023, 15(2), 606. doi: 10.3390/pharmaceutics15020606 PMID: 36839928
  48. M Soliman, S.; Mosallam, S.; Mamdouh, M.A.; Hussein, M.A.; M Abd El-Halim, S. Design and optimization of cranberry extract loaded bile salt augmented liposomes for targeting of MCP-1/STAT3/VEGF signaling pathway in DMN-intoxicated liver in rats. Drug Deliv., 2022, 29(1), 427-439. doi: 10.1080/10717544.2022.2032875 PMID: 35098843
  49. El-Gizawy, H.; Hussein, M. Fatty acids profile, nutritional values, anti-diabetic and antioxidant activity of the fixed oil of malvaparviflora growing in Egypt. Int. J. Phytomed., 2015, 7, 219-230.
  50. Mosaad, Y.O.; Hussein, M.A.; Ateyya, H.; Mohamed, A.H.; Ali, A.A.; Ramadan, Y.A.; Wink, M.; El-Kholy, A.A. Vanin 1 gene role in modulation of iNOS/MCP-1/TGF-β1 signaling pathway in obese diabetic patients. J. Inflamm. Res., 2022, 15, 6745-6759. doi: 10.2147/JIR.S386506 PMID: 36540060
  51. Min, H.Y.; Pei, H.; Hyun, S.Y.; Boo, H.J.; Jang, H.J.; Cho, J.; Kim, J.H.; Son, J.; Lee, H.Y. Potent anticancer effect of the natural steroidal Saponin gracillin is produced by inhibiting glycolysis and oxidative phosphorylation-mediated bioenergetics. Cancers, 2020, 12(4), 913. doi: 10.3390/cancers12040913 PMID: 32276500
  52. Gao, X.; Wang, H.; Yang, J.J.; Liu, X.; Liu, Z.R. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol. Cell, 2012, 45(5), 598-609. doi: 10.1016/j.molcel.2012.01.001 PMID: 22306293
  53. Zheng, L.F.; Dai, F.; Zhou, B.; Yang, L.; Liu, Z.L. Prooxidant activity of hydroxycinnamic acids on DNA damage in the presence of Cu(II) ions: Mechanism and structure–activity relationship. Food Chem. Toxicol., 2008, 46(1), 149-156. doi: 10.1016/j.fct.2007.07.010 PMID: 17764801
  54. Bhosle, S.M.; Huilgol, N.G.; Mishra, K.P. Enhancement of radiation-induced oxidative stress and cytotoxicity in tumor cells by ellagic acid. Clin. Chim. Acta, 2005, 359(1-2), 89-100. doi: 10.1016/j.cccn.2005.03.037 PMID: 15922998
  55. Haupt, S.; Berger, M.; Goldberg, Z.; Haupt, Y. Apoptosis - The p53 network. J. Cell Sci., 2003, 116(20), 4077-4085. doi: 10.1242/jcs.00739 PMID: 12972501
  56. Liu, Y.; Xu, X.; Xu, X.; Li, S.; Liang, Z.; Hu, Z.; Wu, J.; Zhu, Y.; Jin, X.; Wang, X.; Lin, Y.; Chen, H.; Mao, Y.; Luo, J.; Zheng, X.; Xie, L. MicroRNA-193a-3p inhibits cell proliferation in prostate cancer by targeting cyclin D1. Oncol. Lett., 2017, 14(5), 5121-5128. doi: 10.3892/ol.2017.6865 PMID: 29142597
  57. Chen, Z.; Yu, Q.; Chen, G.; Tang, R.; Luo, D.; Dang, Y.; Wei, D. MiR-193a-3p inhibits pancreatic ductal adenocarcinoma cell proliferation by targeting CCND1. Cancer Manag. Res., 2019, 11, 4825-4837. doi: 10.2147/CMAR.S199257 PMID: 31213904
  58. Qian, X.; Li, X.; Lu, Z. Protein kinase activity of the glycolytic enzyme PGK1 regulates autophagy to promote tumorigenesis. Autophagy, 2017, 13(7), 1246-1247. doi: 10.1080/15548627.2017.1313945 PMID: 28486006
  59. Zha, Q.B.; Zhang, X.Y.; Lin, Q.R.; Xu, L.H.; Zhao, G.X.; Pan, H.; Zhou, D.; Ouyang, D.Y.; Liu, Z.H.; He, X.H. Cucurbitacin E induces autophagy via downregulating mTORC1 signaling and upregulating AMPK activity. PLoS One, 2015, 10(5), e0124355. doi: 10.1371/journal.pone.0124355 PMID: 25970614
  60. Zhang, K.; Sun, L.; Kang, Y. Regulation of phosphoglycerate kinase 1 and its critical role in cancer. Cell Commun. Signal., 2023, 21(1), 240. doi: 10.1186/s12964-023-01256-4 PMID: 37723547

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Bentham Science Publishers