A novel amphiphilic squalene-based compound with open-chain polyethers reduces malignant melanoma metastasis in-vitro and in-vivo.
Animals
Mice
Squalene
/ chemistry
Humans
Cell Line, Tumor
Melanoma
/ pathology
Mice, Inbred C57BL
Apoptosis
/ drug effects
Melanoma, Experimental
/ pathology
Neoplasm Metastasis
Lung Neoplasms
/ pathology
Ethers
/ pharmacology
Cell Proliferation
/ drug effects
Tumor Microenvironment
/ drug effects
Skin Neoplasms
/ pathology
Antineoplastic Agents
/ pharmacology
Ethylene glycol
Melanoma
Metastasis
Squalene
Tumor microenvironment
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
11 Sep 2024
11 Sep 2024
Historique:
received:
01
05
2024
accepted:
31
08
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
11
9
2024
Statut:
epublish
Résumé
Squalene (SQ) is a well-known antioxidant and anti-inflammatory agent that provides promising anti-aging and UV-protective roles on human skin. However, its strong hydrophobic nature, accompanied by issues such as poor solubility and limited tissue permeation, has created challenges for scientists to investigate its untapped potential in more complex conditions, including cancer progression. The present study assessed the potent anti-metastatic properties of a newly synthesized amphiphilic ethylene glycol SQ derivative (SQ-diEG) in melanoma, the most fatal skin cancer. In vitro and in vivo experiments have discovered that SQ-diEG may exert its potential on melanoma malignancy through the mitochondria-mediated caspase activation apoptotic signaling pathway. The potent anti-metastatic effect of SQ-diEG was observed in vitro using highly proliferative and aggressive melanoma cells. Administration of SQ-diEG (25 mg/kg) significantly decreased the tumor burden on the lung and inhibited the metastasis-associated proteins and gene markers in B16F10 lung colonization mice model. Furthermore, global gene profiling also revealed a promising role of SQ-diEG in tumor microenvironment. We anticipated that the amphiphilic nature of the SQ compound bearing ethylene glycol oligomers could potentially augment its ability to reach the pathology site, thus enhancing its therapeutic potential in melanoma.
Identifiants
pubmed: 39261954
doi: 10.1186/s12964-024-01813-5
pii: 10.1186/s12964-024-01813-5
doi:
Substances chimiques
Squalene
7QWM220FJH
Ethers
0
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
437Informations de copyright
© 2024. The Author(s).
Références
Saginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. Epidemiology of Melanoma Medical Sciences. 2021;9:63.
pubmed: 34698235
doi: 10.3390/medsci9040063
Gil D, Ciołczyk-Wierzbicka D, Dulińska-Litewka J, Żwawa K, McCubrey JA, Laidler P. The mechanism of contribution of integrin linked kinase (ILK) to epithelial-mesenchymal transition (EMT). Adv Enzyme Regul. 2011;51:195–207.
pubmed: 21035499
doi: 10.1016/j.advenzreg.2010.09.005
Koop S, MacDonald IC, Luzzi K, Schmidt EE, Morris VL, Grattan M, et al. Fate of Melanoma Cells Entering the Microcirculation: Over 80% Survive and Extravasate1. Can Res. 1995;55:2520–3.
Nicolson GL. Cancer metastasis: Organ colonization and the cell-surface properties of mallignant cells. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1982;695:113–76.
Mahabeleshwar GH, Byzova TV. Angiogenesis in Melanoma. Semin Oncol. 2007;34:555–65.
pubmed: 18083379
pmcid: 2365306
doi: 10.1053/j.seminoncol.2007.09.009
Kessenbrock K, Plaks V, Werb Z. Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. Cell. 2010;141:52–67.
pubmed: 20371345
pmcid: 2862057
doi: 10.1016/j.cell.2010.03.015
Hofmann UB, Westphal JR, van Muijen GNP, Ruiter DJ. Matrix Metalloproteinases in Human Melanoma. J Investig Dermatol. 2000;115:337–44.
pubmed: 10951266
doi: 10.1046/j.1523-1747.2000.00068.x
Nobili S, Lippi D, Witort E, Donnini M, Bausi L, Mini E, et al. Natural compounds for cancer treatment and prevention. Pharmacol Res. 2009;59:365–78.
pubmed: 19429468
doi: 10.1016/j.phrs.2009.01.017
Kang T-H, Yoon G, Kang I-A, Oh H-N, Chae J-I, Shim J-H. Natural Compound Licochalcone B Induced Extrinsic and Intrinsic Apoptosis in Human Skin Melanoma (A375) and Squamous Cell Carcinoma (A431) Cells. Phytother Res. 2017;31:1858–67.
pubmed: 29027311
doi: 10.1002/ptr.5928
Sztiller-Sikorska M, Koprowska K, Majchrzak K, Hartman M, Czyz M. Natural Compounds’ Activity against Cancer Stem-Like or Fast-Cycling Melanoma Cells. PLoS ONE. 2014;9: e90783.
pubmed: 24595456
pmcid: 3940936
doi: 10.1371/journal.pone.0090783
Huang C-H, Lu S-H, Chang C-C, Thomas PA, Jayakumar T, Sheu J-R. Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16–F10) cell migration and in vivo tumor formation. Eur J Pharmacol. 2015;746:148–57.
pubmed: 25449038
doi: 10.1016/j.ejphar.2014.11.011
Deng L-J, Qi M, Li N, Lei Y-H, Zhang D-M, Chen J-X. Natural products and their derivatives: Promising modulators of tumor immunotherapy. J Leukoc Biol. 2020;108:493–508.
pubmed: 32678943
doi: 10.1002/JLB.3MR0320-444R
Poornima P, Kumar JD, Zhao Q, Blunder M, Efferth T. Network pharmacology of cancer: From understanding of complex interactomes to the design of multi-target specific therapeutics from nature. Pharmacol Res. 2016;111:290–302.
pubmed: 27329331
doi: 10.1016/j.phrs.2016.06.018
Kaya K, Nakazawa A, Matsuura H, Honda D, Inouye I, Watanabe MM. Thraustochytrid Aurantiochytrium sp. 18W–13a Accummulates High Amounts of Squalene. Biosci Biotechnol Biochem. 2011;75:2246–8.
pubmed: 22056449
doi: 10.1271/bbb.110430
Kelly GS. Squalene and its potential clinical uses. Alternative medicine review: a journal of clinical therapeutic. 1999;4:29–36.
pubmed: 9988781
Ronco AL, Stéfani ED. Squalene: a multi-task link in the crossroads of cancer and aging. Functional Foods in Health and Disease. 2013;3:462.
doi: 10.31989/ffhd.v3i12.30
Rao CV, Newmark HL, Reddy BS. Chemopreventive effect of squalene on colon cancer. Carcinogenesis. 1998;19:287–90.
pubmed: 9498278
doi: 10.1093/carcin/19.2.287
Linh TN, Arimura T, Tominaga K, Kigoshi H, Isoda H. Syntheses and aggregation properties of new squalene receptors bearing open chain ligands. Supramol Chem. 2021;33:194–201.
doi: 10.1080/10610278.2021.1970161
Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, et al. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50:W216–21.
pubmed: 35325185
pmcid: 9252805
doi: 10.1093/nar/gkac194
Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.
pubmed: 30944313
pmcid: 6447622
doi: 10.1038/s41467-019-09234-6
Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, et al. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol. 2015;35:S25–54.
pubmed: 25892662
pmcid: 4898971
doi: 10.1016/j.semcancer.2015.02.006
Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.
pubmed: 10653597
doi: 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9
Theodosakis N, Micevic G, Kelly DP, Bosenberg M. Mitochondrial function in melanoma. Arch Biochem Biophys. 2014;563:56–9.
pubmed: 24997363
doi: 10.1016/j.abb.2014.06.028
Zorova LD, Popkov VA, Plotnikov EY, Silachev DN, Pevzner IB, Jankauskas SS, et al. Mitochondrial membrane potential. Anal Biochem. 2018;552:50–9.
pubmed: 28711444
doi: 10.1016/j.ab.2017.07.009
Lu P, Weaver VM, Werb Z. The extracellular matrix: A dynamic niche in cancer progression. J Cell Biol. 2012;196:395–406.
pubmed: 22351925
pmcid: 3283993
doi: 10.1083/jcb.201102147
Dhanasekaran R, Deutzmann A, Mahauad-Fernandez WD, Hansen AS, Gouw AM, Felsher DW. The MYC oncogene — the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol. 2022;19:23–36.
pubmed: 34508258
doi: 10.1038/s41571-021-00549-2
Shen L, Chen Q, Yang C, Wu Y, Yuan H, Chen S, et al. Role of PRDM1 in tumor immunity and drug response: a pan-cancer analysis. Front Pharmacol. 2020;11: 593195.
pubmed: 33384601
pmcid: 7770985
doi: 10.3389/fphar.2020.593195
Kerr JFR, Winterford CM, Harmon BV. Apoptosis. Its significance in cancer and cancer Therapy. Cancer. 1994;73:2013–26.
pubmed: 8156506
doi: 10.1002/1097-0142(19940415)73:8<2013::AID-CNCR2820730802>3.0.CO;2-J
Lakhani SA, Masud A, Kuida K, Porter GA, Booth CJ, Mehal WZ, et al. Caspases 3 and 7: Key Mediators of Mitochondrial Events of Apoptosis. Science. 2006;311:847–51.
pubmed: 16469926
pmcid: 3738210
doi: 10.1126/science.1115035
Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol. 2019;20:175–93.
pubmed: 30655609
pmcid: 7325303
doi: 10.1038/s41580-018-0089-8
Velho TR. Metastatic melanoma – a review of current and future drugs. Drugs Context. 2012;2012: 212242.
pubmed: 24432031
pmcid: 3885142
Senevirathne SA, Washington KE, Biewer MC, Stefan MC. PEG based anti-cancer drug conjugated prodrug micelles for the delivery of anti-cancer agents. J Mater Chem B. 2016;4:360–70.
pubmed: 32263202
doi: 10.1039/C5TB02053K
Zhang X, Wang H, Ma Z, Wu B. Effects of pharmaceutical PEGylation on drug metabolism and its clinical concerns. Expert Opin Drug Metab Toxicol. 2014;10:1691–702.
pubmed: 25270687
doi: 10.1517/17425255.2014.967679
Strandberg T, Tilvis R, Miettinen T. Metabolic variables of cholesterol during squalene feeding in humans: comparison with cholestyramine treatment. J Lipid Res. 1990;31:1637–43.
pubmed: 2246614
doi: 10.1016/S0022-2275(20)42347-8
Spano D, Zollo M. Tumor microenvironment: a main actor in the metastasis process. Clin Exp Metastasis. 2012;29:381–95.
pubmed: 22322279
doi: 10.1007/s10585-012-9457-5
Hofmann UB, Eggert AAO, Blass K, Bröcker E-B, Becker JC. Expression of Matrix Metalloproteinases in the Microenvironment of Spontaneous and Experimental Melanoma Metastases Reflects the Requirements for Tumor Formation. Can Res. 2003;63:8221–5.
Yu D, Lai P, Yan T, Fang K, Chen L, Zhang S. Quantifying the Matrix Metalloproteinase 2 (MMP2) Spatially in Tissues by Probe via MALDI Imaging Mass Spectrometry. Front Chem. 2021;9: 786283.
pubmed: 34976953
pmcid: 8715900
doi: 10.3389/fchem.2021.786283
Möser CV, Meissner M, Laarmann K, Olbrich K, King-Himmelreich TS, Wolters MC, et al. The protein kinase IKKepsilon contributes to tumour growth and tumour pain in a melanoma model. Biochem Pharmacol. 2016;103:64–73.
pubmed: 26793999
doi: 10.1016/j.bcp.2015.12.016
Yin M, Wang X, Lu J. Advances in IKBKE as a potential target for cancer therapy. Cancer Med. 2020;9:247–58.
pubmed: 31733040
doi: 10.1002/cam4.2678
Zerfaoui M, Toraih E, Ruiz E, Errami Y, Attia AS, Krzysztof M, et al. Nuclear Localization of BRAFV600E Is Associated with HMOX-1 Upregulation and Aggressive Behavior of Melanoma Cells. Cancers. 2022;14:311.
pubmed: 35053476
pmcid: 8773521
doi: 10.3390/cancers14020311
Karras P, Riveiro-Falkenbach E, Cañón E, Tejedo C, Calvo TG, Martínez-Herranz R, et al. p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors. Cancer Cell. 2019;35:46–63.e10.
pubmed: 30581152
doi: 10.1016/j.ccell.2018.11.008
Boström K, Zebboudj AF, Yao Y, Lin TS, Torres A. Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells *. J Biol Chem. 2004;279:52904–13.
pubmed: 15456771
doi: 10.1074/jbc.M406868200
Gerarduzzi C, Hartmann U, Leask A, Drobetsky E. The Matrix Revolution: Matricellular Proteins and Restructuring of the Cancer Microenvironment. Can Res. 2020;80:2705–17.
doi: 10.1158/0008-5472.CAN-18-2098
Ganzetti G, Sartini D, Campanati A, Rubini C, Molinelli E, Brisigotti V, et al. Nicotinamide N-methyltransferase: potential involvement in cutaneous malignant melanoma. Melanoma Res. 2018;28:82.
pubmed: 29420365
doi: 10.1097/CMR.0000000000000430
Wu X, Nelson M, Basu M, Srinivasan P, Lazarski C, Zhang P, et al. MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination. J Immunother Cancer. 2021;9: e001388.
pubmed: 33757986
pmcid: 7993333
doi: 10.1136/jitc-2020-001388
Li Q, Zhang L, You W, Xu J, Dai J, Hua D, et al. PRDM1/BLIMP1 induces cancer immune evasion by modulating the USP22-SPI1-PD-L1 axis in hepatocellular carcinoma cells. Nat Commun. 2022;13:7677.
pubmed: 36509766
pmcid: 9744896
doi: 10.1038/s41467-022-35469-x
Richmond A, Yang J, Su Y. The good and the bad of chemokines/chemokine receptors in melanoma. Pigment Cell Melanoma Res. 2009;22:175–86.
pubmed: 19222802
pmcid: 2848967
doi: 10.1111/j.1755-148X.2009.00554.x
Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling U, Kobert N, Schaerer L, et al. In vivo Switching of Human Melanoma Cells between Proliferative and Invasive States. Can Res. 2008;68:650–6.
doi: 10.1158/0008-5472.CAN-07-2491
Perego M, Maurer M, Wang JX, Shaffer S, Müller AC, Parapatics K, et al. A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene. 2018;37:302–12.
pubmed: 28925403
doi: 10.1038/onc.2017.341
Shapiro GI, Harper JW. Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest. 1999;104:1645–53.
pubmed: 10606615
pmcid: 409893
doi: 10.1172/JCI9054
Yano S, Miwa S, Mii S, Hiroshima Y, Uehara F, Yamamoto M, et al. Invading cancer cells are predominantly in G0/G1 resulting in chemoresistance demonstrated by real-time FUCCI imaging. Cell Cycle. 2014;13:953–60.
pubmed: 24552821
pmcid: 3984318
doi: 10.4161/cc.27818
Chen J. The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harb Perspect Med. 2016;6: a026104.
pubmed: 26931810
pmcid: 4772082
doi: 10.1101/cshperspect.a026104
Yadav UP, Singh T, Kumar P, Sharma P, Kaur H, Sharma S, et al. Metabolic Adaptations in Cancer Stem Cells. Front Oncol. 2020;10:1010.
pubmed: 32670883
pmcid: 7330710
doi: 10.3389/fonc.2020.01010
Begum HM, Shen K. Intracellular and microenvironmental regulation of mitochondrial membrane potential in cancer cells. WIREs Mechanisms of Disease. 2023;15: e1595.
pubmed: 36597256
pmcid: 10176868
doi: 10.1002/wsbm.1595
Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (Δψm) in apoptosis; an update. Apoptosis. 2003;8:115–28.
pubmed: 12766472
doi: 10.1023/A:1022945107762
Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochemical Journal. 1999;341:233–49.
pubmed: 10393078
pmcid: 1220352
doi: 10.1042/bj3410233
Pflaum J, Schlosser S, Müller M. p53 Family and Cellular Stress Responses in Cancer. Front Oncol. 2014;4:285.
pubmed: 25374842
pmcid: 4204435
doi: 10.3389/fonc.2014.00285
Herr I, Debatin K-M. Cellular stress response and apoptosis in cancer therapy. Blood. 2001;98:2603–14.
pubmed: 11675328
doi: 10.1182/blood.V98.9.2603
Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, et al. p53 Has a Direct Apoptogenic Role at the Mitochondria. Mol Cell. 2003;11:577–90.
pubmed: 12667443
doi: 10.1016/S1097-2765(03)00050-9
Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7:880–5.
pubmed: 16953201
pmcid: 1559676
doi: 10.1038/sj.embor.7400779
Neill G, Masson GR. A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response. Front Mol Neurosci. 2023;16:1112253.
pubmed: 36825279
pmcid: 9941348
doi: 10.3389/fnmol.2023.1112253
Pihán P, Carreras-Sureda A, Hetz C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 2017;24:1478–87.
pubmed: 28622296
pmcid: 5563989
doi: 10.1038/cdd.2017.82
Powell E, Piwnica-Worms D, Piwnica-Worms H. Contribution of p53 to metastasis. Cancer Discov. 2014;4:405–14.
pubmed: 24658082
pmcid: 4063123
doi: 10.1158/2159-8290.CD-13-0136
Bagheri-Yarmand R, Williams MD, Grubbs EG, Gagel RF. ATF4 targets RET for degradation and is a candidate tumor suppressor gene in medullary thyroid cancer. J Clin Endocrinol Metab. 2017;102:933–41.
pubmed: 27935748
Chen J, Huang X, Zhang S, Zhu X. ATF4 inhibits tumor development and mediates p-GCN2/ASNS upregulation in colon cancer. Sci Rep. 2024;14:13042.
pubmed: 38844625
pmcid: 11156644
doi: 10.1038/s41598-024-63895-y
Armstrong JL, Flockhart R, Veal GJ, Lovat PE, Redfern CP. Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. J Biol Chem. 2010;285:6091–100.
pubmed: 20022965
doi: 10.1074/jbc.M109.014092