Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.
Cancer
Complex I
N-myristoylation
N-myristoyltransferase
NDUFAF4
NMT inhibitor (NMTI)
Oxidative phosphorylation
PCLX-001 (zelenirstat)
Respiration
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
13
11
2023
accepted:
31
03
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
epublish
Résumé
In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
Sections du résumé
BACKGROUND
BACKGROUND
In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.
METHODS AND RESULTS
RESULTS
Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.
CONCLUSIONS
CONCLUSIONS
Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
Identifiants
pubmed: 38715059
doi: 10.1186/s12967-024-05150-6
pii: 10.1186/s12967-024-05150-6
doi:
Substances chimiques
Acyltransferases
EC 2.3.-
glycylpeptide N-tetradecanoyltransferase
EC 2.3.1.97
Myristic Acid
0I3V7S25AW
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
431Subventions
Organisme : Alberta Cancer Foundation
ID : 26362
Organisme : Alberta Cancer Foundation
ID : 26927
Organisme : Alberta Innovates - Health Solutions
ID : Translational Health Chair
Informations de copyright
© 2024. The Author(s).
Références
Yang SH, Shrivastav A, Kosinski C, Sharma RK, Chen MH, Berthiaume LG, Peters LL, Chuang PT, Young SG, Bergo MO. N-myristoyltransferase 1 is essential in early mouse development. J Biol Chem. 2005;280:18990–5.
pubmed: 15753093
doi: 10.1074/jbc.M412917200
Deichaite I, Casson LP, Ling HP, Resh MD. In vitro synthesis of pp60v-src: myristylation in a cell-free system. Mol Cell Biol. 1988;8:4295–301.
pubmed: 3141787
pmcid: 365502
Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science. 2000;290:1761–5.
pubmed: 11099414
doi: 10.1126/science.290.5497.1761
Taniguchi H. Protein myristoylation in protein-lipid and protein-protein interactions. Biophys Chem. 1999;82:129–37.
pubmed: 10631796
doi: 10.1016/S0301-4622(99)00112-X
McCabe JB, Berthiaume LG. N-terminal protein acylation confers localization to cholesterol, sphingolipid-enriched membranes but not to lipid rafts/caveolae. Mol Biol Cell. 2001;12:3601–17.
pubmed: 11694592
pmcid: 60279
doi: 10.1091/mbc.12.11.3601
Burnaevskiy N, Fox TG, Plymire DA, Ertelt JM, Weigele BA, Selyunin AS, Way SS, Patrie SM, Alto NM. Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. Nature. 2013;496:106–9.
pubmed: 23535599
pmcid: 3722872
doi: 10.1038/nature12004
Schwertassek U, Buckley DA, Xu CF, Lindsay AJ, McCaffrey MW, Neubert TA, Tonks NK. Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis. FEBS J. 2010;277:2463–73.
pubmed: 20553486
pmcid: 2894504
doi: 10.1111/j.1742-4658.2010.07661.x
Vilas GL, Corvi MM, Plummer GJ, Seime AM, Lambkin GR, Berthiaume LG. Posttranslational myristoylation of caspase-activated p21-activated protein kinase 2 (PAK2) potentiates late apoptotic events. Proc Natl Acad Sci U S A. 2006;103:6542–7.
pubmed: 16617111
pmcid: 1458920
doi: 10.1073/pnas.0600824103
Giang DK, Cravatt BF. A second mammalian N-myristoyltransferase. J Biol Chem. 1998;273:6595–8.
pubmed: 9506952
doi: 10.1074/jbc.273.12.6595
Tate EW, Kalesh KA, Lanyon-Hogg T, Storck EM, Thinon E. Global profiling of protein lipidation using chemical proteomic technologies. Curr Opin Chem Biol. 2015;24:48–57.
pubmed: 25461723
pmcid: 4319709
doi: 10.1016/j.cbpa.2014.10.016
Buss JE, Kamps MP, Sefton BM. Myristic acid is attached to the transforming protein of Rous sarcoma virus during or immediately after synthesis and is present in both soluble and membrane-bound forms of the protein. Mol Cell Biol. 1984;4:2697–704.
pubmed: 6441887
pmcid: 369279
Jackson P, Baltimore D. N-terminal mutations activate the leukemogenic potential of the myristoylated form of c-abl. EMBO J. 1989;8:449–56.
pubmed: 2542016
pmcid: 400826
doi: 10.1002/j.1460-2075.1989.tb03397.x
Sigal CT, Zhou W, Buser CA, McLaughlin S, Resh MD. Amino-terminal basic residues of Src mediate membrane binding through electrostatic interaction with acidic phospholipids. Proc Natl Acad Sci U S A. 1994;91:12253–7.
pubmed: 7527558
pmcid: 45415
doi: 10.1073/pnas.91.25.12253
Selvakumar P, Lakshmikuttyamma A, Shrivastav A, Das SB, Dimmock JR, Sharma RK. Potential role of N-myristoyltransferase in cancer. Prog Lipid Res. 2007;46:1–36.
pubmed: 16846646
doi: 10.1016/j.plipres.2006.05.002
Díaz B, Ostapoff KT, Toombs JE, Lo J, Bonner MY, Curatolo A, Adsay V, Brekken RA, Arbiser JL. Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model. Oncotarget. 2016;7:51569–80.
pubmed: 27438140
pmcid: 5239497
doi: 10.18632/oncotarget.10514
Kim S, Alsaidan OA, Goodwin O, Li Q, Sulejmani E, Han Z, Bai A, Albers T, Beharry Z, Zheng YGG, et al. Blocking myristoylation of Src inhibits its kinase activity and suppresses prostate cancer progression. Cancer Res. 2017;77:6950–62.
pubmed: 29038344
pmcid: 5732839
doi: 10.1158/0008-5472.CAN-17-0981
Tan XP, He Y, Yang J, Wei X, Fan YL, Zhang GG, Zhu YD, Li ZQ, Liao HX, Qin DJ, et al. Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression. Signal Transduct Target Ther. 2023;8:14.
pubmed: 36617552
pmcid: 9826789
doi: 10.1038/s41392-022-01248-9
Kallemeijn WW, Lueg GA, Faronato M, Hadavizadeh K, Goya Grocin A, Song OR, Howell M, Calado DP, Tate EW. Validation and invalidation of chemical probes for the human N-myristoyltransferases. Cell Chem Biol. 2019;26(892–900): e894.
Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science. 2019;365:eaaw4912.
pubmed: 31273098
pmcid: 7090375
doi: 10.1126/science.aaw4912
Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, Price HP, Guther ML, Torrie LS, Robinson DA, et al. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature. 2010;464:728–32.
pubmed: 20360736
pmcid: 2917743
doi: 10.1038/nature08893
Sangha R, Davies NM, Namdar A, Chu M, Spratlin J, Beauchamp E, Berthiaume LG, Mackey JR. Novel, first-in-human, oral PCLX-001 treatment in a patient with relapsed diffuse large B-cell lymphoma. Curr Oncol. 2022;29:1939–46.
pubmed: 35323358
pmcid: 8947478
doi: 10.3390/curroncol29030158
Beauchamp E, Yap MC, Iyer A, Perinpanayagam MA, Gamma JM, Vincent KM, Lakshmanan M, Raju A, Tergaonkar V, Tan SY, et al. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat Commun. 2020;11:5348.
pubmed: 33093447
pmcid: 7582192
doi: 10.1038/s41467-020-18998-1
Mackey JR, Lai J, Chauhan U, Beauchamp E, Dong WF, Glubrecht D, Sim YW, Ghosh S, Bigras G, Lai R, Berthiaume LG. N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug target. Breast Cancer Res Treat. 2021;186:79–87.
pubmed: 33398478
pmcid: 7940342
doi: 10.1007/s10549-020-06037-y
Kaelin WG Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689–98.
pubmed: 16110319
doi: 10.1038/nrc1691
Gry M, Rimini R, Strömberg S, Asplund A, Pontén F, Uhlén M, Nilsson P. Correlations between RNA and protein expression profiles in 23 human cell lines. BMC Genomics. 2009;10:365.
pubmed: 19660143
pmcid: 2728742
doi: 10.1186/1471-2164-10-365
Dempster JM, Boyle I, Vazquez F, Root DE, Boehm JS, Hahn WC, Tsherniak A, McFarland JM. Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects. Genome Biol. 2021;22:343.
pubmed: 34930405
pmcid: 8686573
doi: 10.1186/s13059-021-02540-7
Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, Tzankov A, Wen W, Liu WM, Kahl BS, d’Amore ES, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26:2103–13.
pubmed: 22437443
pmcid: 3637886
doi: 10.1038/leu.2012.83
Li Y, Tollefsbol TO. DNA methylation detection: bisulfite genomic sequencing analysis. Methods Mol Biol. 2011;791:11–21.
pubmed: 21913068
pmcid: 3233226
doi: 10.1007/978-1-61779-316-5_2
Boultwood J, Wainscoat JS. Gene silencing by DNA methylation in haematological malignancies. Br J Haematol. 2007;138:3–11.
pubmed: 17489980
doi: 10.1111/j.1365-2141.2007.06604.x
Cameron EE, Bachman KE, Myöhänen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–7.
pubmed: 9916800
doi: 10.1038/5047
Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S, Bindal N, Beare D, Smith JA, Thompson IR, et al. Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2013;41:D955–61.
pubmed: 23180760
doi: 10.1093/nar/gks1111
Wang Q, Armenia J, Zhang C, Penson AV, Reznik E, Zhang L, Minet T, Ochoa A, Gross BE, Iacobuzio-Donahue CA, et al. Unifying cancer and normal RNA sequencing data from different sources. Sci Data. 2018;5: 180061.
pubmed: 29664468
pmcid: 5903355
doi: 10.1038/sdata.2018.61
McDermott M, Eustace AJ, Busschots S, Breen L, Crown J, Clynes M, O’Donovan N, Stordal B. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies. Front Oncol. 2014;4:40.
pubmed: 24639951
pmcid: 3944788
doi: 10.3389/fonc.2014.00040
Aubrey BJ, Kelly GL, Kueh AJ, Brennan MS, O’Connor L, Milla L, Wilcox S, Tai L, Strasser A, Herold MJ. An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo. Cell Rep. 2015;10:1422–32.
pubmed: 25732831
doi: 10.1016/j.celrep.2015.02.002
Cabello-Rivera D, Sarmiento-Soto H, López-Barneo J, Muñoz-Cabello AM. Mitochondrial complex I function is essential for neural stem/progenitor cells proliferation and differentiation. Front Neurosci. 2019;13:664.
pubmed: 31297047
pmcid: 6607990
doi: 10.3389/fnins.2019.00664
Bi G, Bian Y, Liang J, Yin J, Li R, Zhao M, Huang Y, Lu T, Zhan C, Fan H, Wang Q. Pan-cancer characterization of metabolism-related biomarkers identifies potential therapeutic targets. J Transl Med. 2021;19:219.
pubmed: 34030708
pmcid: 8142489
doi: 10.1186/s12967-021-02889-0
Oshi M, Patel A, Wu R, Le L, Tokumaru Y, Yamada A, Yan L, Matsuyama R, Ishikawa T, Endo I, Takabe K. Enhanced immune response outperform aggressive cancer biology and is associated with better survival in triple-negative breast cancer. NPJ Breast Cancer. 2022;8:92.
pubmed: 35945417
pmcid: 9363489
doi: 10.1038/s41523-022-00466-2
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
Nakajima R, Zhao L, Zhou Y, Shirasawa M, Uchida A, Murakawa H, Fikriyanti M, Iwanaga R, Bradford AP, Araki K, et al. Deregulated E2F activity as a cancer-cell specific therapeutic tool. Genes (Basel). 2023;14:393.
pubmed: 36833320
pmcid: 9956157
doi: 10.3390/genes14020393
Ahmadi SE, Rahimi S, Zarandi B, Chegeni R, Safa M. MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies. J Hematol Oncol. 2021;14:121.
pubmed: 34372899
pmcid: 8351444
doi: 10.1186/s13045-021-01111-4
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–60.
pubmed: 31114875
pmcid: 6602440
doi: 10.1093/nar/gkz430
Li Y, Umbach DM, Krahn JM, Shats I, Li X, Li L. Predicting tumor response to drugs based on gene-expression biomarkers of sensitivity learned from cancer cell lines. BMC Genomics. 2021;22:272.
pubmed: 33858332
pmcid: 8048084
doi: 10.1186/s12864-021-07581-7
Mrozek-Gorska P, Buschle A, Pich D, Schwarzmayr T, Fechtner R, Scialdone A, Hammerschmidt W. Epstein-Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc Natl Acad Sci U S A. 2019;116:16046–55.
pubmed: 31341086
pmcid: 6690029
doi: 10.1073/pnas.1901314116
Qin H, Ni H, Liu Y, Yuan Y, Xi T, Li X, Zheng L. RNA-binding proteins in tumor progression. J Hematol Oncol. 2020;13:90.
pubmed: 32653017
pmcid: 7353687
doi: 10.1186/s13045-020-00927-w
El Khoury W, Nasr Z. Deregulation of ribosomal proteins in human cancers. Biosci Rep. 2021;41:BSR20211577.
pubmed: 34873618
pmcid: 8685657
doi: 10.1042/BSR20211577
van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10:301–9.
pubmed: 20332779
doi: 10.1038/nrc2819
Sullivan DK, Deutzmann A, Yarbrough J, Krishnan MS, Gouw AM, Bellovin DI, Adam SJ, Liefwalker DF, Dhanasekaran R, Felsher DW. MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes. Oncogene. 2022;41:4960–70.
pubmed: 36207533
pmcid: 10257951
doi: 10.1038/s41388-022-02458-9
Dong Y, Tu R, Liu H, Qing G. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Signal Transduct Target Ther. 2020;5:124.
pubmed: 32651356
pmcid: 7351732
doi: 10.1038/s41392-020-00235-2
Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O’Donnell KA, Kim JW, Yustein JT, Lee LA, Dang CV. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol. 2005;25:6225–34.
pubmed: 15988031
pmcid: 1168798
doi: 10.1128/MCB.25.14.6225-6234.2005
Graves JA, Wang Y, Sims-Lucas S, Cherok E, Rothermund K, Branca MF, Elster J, Beer-Stolz D, Van Houten B, Vockley J, Prochownik EV. Mitochondrial structure, function and dynamics are temporally controlled by c-Myc. PLoS ONE. 2012;7: e37699.
pubmed: 22629444
pmcid: 3357432
doi: 10.1371/journal.pone.0037699
Sun Y, Guan Z, Sheng Q, Duan W, Zhao H, Zhou J, Deng Q, Pei X. N-myristoyltransferase-1 deficiency blocks myristoylation of LAMTOR1 and inhibits bladder cancer progression. Cancer Lett. 2022;529:126–38.
pubmed: 34999170
doi: 10.1016/j.canlet.2022.01.001
Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-modified cancer cell metabolism. Front Cell Dev Biol. 2019;7:4.
pubmed: 30761299
pmcid: 6362613
doi: 10.3389/fcell.2019.00004
Yu L, Chen X, Sun X, Wang L, Chen S. The glycolytic switch in tumors: how many players are involved? J Cancer. 2017;8:3430–40.
pubmed: 29151926
pmcid: 5687156
doi: 10.7150/jca.21125
Ali N, Ling N, Krishnamurthy S, Oakhill JS, Scott JW, Stapleton DI, Kemp BE, Anand GS, Gooley PR. β-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase. Sci Rep. 2016;6:39417.
pubmed: 28000716
pmcid: 5175161
doi: 10.1038/srep39417
Liang J, Xu ZX, Ding Z, Lu Y, Yu Q, Werle KD, Zhou G, Park YY, Peng G, Gambello MJ, Mills GB. Myristoylation confers noncanonical AMPK functions in autophagy selectivity and mitochondrial surveillance. Nat Commun. 2015;6:7926.
pubmed: 26272043
doi: 10.1038/ncomms8926
Thinon E, Morales-Sanfrutos J, Mann DJ, Tate EW. N-myristoyltransferase inhibition induces ER-stress, cell cycle arrest, and apoptosis in cancer cells. ACS Chem Biol. 2016;11:2165–76.
pubmed: 27267252
pmcid: 5077176
doi: 10.1021/acschembio.6b00371
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13:89–102.
pubmed: 22251901
doi: 10.1038/nrm3270
Fuhrmann DC, Brüne B. Mitochondrial composition and function under the control of hypoxia. Redox Biol. 2017;12:208–15.
pubmed: 28259101
pmcid: 5333533
doi: 10.1016/j.redox.2017.02.012
Liu B, Chen Y, St Clair DK. ROS and p53: a versatile partnership. Free Radic Biol Med. 2008;44:1529–35.
pubmed: 18275858
pmcid: 2359898
doi: 10.1016/j.freeradbiomed.2008.01.011
Utsumi T, Matsuzaki K, Kiwado A, Tanikawa A, Kikkawa Y, Hosokawa T, Otsuka A, Iuchi Y, Kobuchi H, Moriya K. Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PLoS ONE. 2018;13: e0206355.
pubmed: 30427857
pmcid: 6235283
doi: 10.1371/journal.pone.0206355
Tang J, Zhang K, Dong J, Yan C, Hu C, Ji H, Chen L, Chen S, Zhao H, Song Z. Sam50-Mic19-Mic60 axis determines mitochondrial cristae architecture by mediating mitochondrial outer and inner membrane contact. Cell Death Differ. 2020;27:146–60.
pubmed: 31097788
doi: 10.1038/s41418-019-0345-2
Cogliati S, Enriquez JA, Scorrano L. Mitochondrial cristae: where beauty meets functionality. Trends Biochem Sci. 2016;41:261–73.
pubmed: 26857402
doi: 10.1016/j.tibs.2016.01.001
Djeungoue-Petga MA, Lurette O, Jean S, Hamel-Côté G, Martín-Jiménez R, Bou M, Cannich A, Roy P, Hebert-Chatelain E. Intramitochondrial Src kinase links mitochondrial dysfunctions and aggressiveness of breast cancer cells. Cell Death Dis. 2019;10:940.
pubmed: 31819039
pmcid: 6901437
doi: 10.1038/s41419-019-2134-8
Guedouari H, Savoie MC, Jean S, Djeungoue-Petga MA, Pichaud N, Hebert-Chatelain E. Multi-omics reveal that c-Src modulates the mitochondrial phosphotyrosine proteome and metabolism according to nutrient availability. Cell Physiol Biochem. 2020;54:517–37.
pubmed: 32428391
doi: 10.33594/000000237
Hebert-Chatelain E. Src kinases are important regulators of mitochondrial functions. Int J Biochem Cell Biol. 2013;45:90–8.
pubmed: 22951354
doi: 10.1016/j.biocel.2012.08.014
Greuber EK, Smith-Pearson P, Wang J, Pendergast AM. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer. 2013;13:559–71.
pubmed: 23842646
pmcid: 3935732
doi: 10.1038/nrc3563
Chiu CL, Zhao H, Chen CH, Wu R, Brooks JD. The role of MARCKS in metastasis and treatment resistance of solid tumors. Cancers (Basel). 2022;14:4925.
pubmed: 36230850
doi: 10.3390/cancers14194925
Tang H, Wang Y, Zhang B, Xiong S, Liu L, Chen W, Tan G, Li H. High brain acid soluble protein 1(BASP1) is a poor prognostic factor for cervical cancer and promotes tumor growth. Cancer Cell Int. 2017;17:97.
pubmed: 29089860
pmcid: 5655910
doi: 10.1186/s12935-017-0452-4
Neumann-Giesen C, Falkenbach B, Beicht P, Claasen S, Lüers G, Stuermer CA, Herzog V, Tikkanen R. Membrane and raft association of reggie-1/flotillin-2: role of myristoylation, palmitoylation and oligomerization and induction of filopodia by overexpression. Biochem J. 2004;378:509–18.
pubmed: 14599293
pmcid: 1223955
doi: 10.1042/bj20031100
Saeki K, Miura Y, Aki D, Kurosaki T, Yoshimura A. The B cell-specific major raft protein, Raftlin, is necessary for the integrity of lipid raft and BCR signal transduction. EMBO J. 2003;22:3015–26.
pubmed: 12805216
pmcid: 162145
doi: 10.1093/emboj/cdg293
Liu Y, Kahn RA, Prestegard JH. Structure and membrane interaction of myristoylated ARF1. Structure. 2009;17:79–87.
pubmed: 19141284
pmcid: 2659477
doi: 10.1016/j.str.2008.10.020
Voisset E, Brenet F, Lopez S, de Sepulveda P. SRC-family kinases in acute myeloid leukaemia and mastocytosis. Cancers (Basel). 2020;12:1996.
pubmed: 32708273
doi: 10.3390/cancers12071996
Alvarez RH, Kantarjian HM, Cortes JE. The role of Src in solid and hematologic malignancies: development of new-generation Src inhibitors. Cancer. 2006;107:1918–29.
pubmed: 16986126
doi: 10.1002/cncr.22215
Martellucci S, Clementi L, Sabetta S, Mattei V, Botta L, Angelucci A. Src family kinases as therapeutic targets in advanced solid tumors: what we have learned so far. Cancers (Basel). 2020;12:1448.
pubmed: 32498343
doi: 10.3390/cancers12061448
Montero JC, Seoane S, Ocaña A, Pandiella A. Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. Clin Cancer Res. 2011;17:5546–52.
pubmed: 21670084
doi: 10.1158/1078-0432.CCR-10-2616
Giaccone G, Zucali PA. Src as a potential therapeutic target in non-small-cell lung cancer. Ann Oncol. 2008;19:1219–23.
pubmed: 18388349
doi: 10.1093/annonc/mdn048
Konig H, Copland M, Chu S, Jove R, Holyoake TL, Bhatia R. Effects of dasatinib on SRC kinase activity and downstream intracellular signaling in primitive chronic myelogenous leukemia hematopoietic cells. Cancer Res. 2008;68:9624–33.
pubmed: 19047139
pmcid: 2786265
doi: 10.1158/0008-5472.CAN-08-1131
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.
pubmed: 19872213
pmcid: 2140820
doi: 10.1085/jgp.8.6.519
Calabrese C, Iommarini L, Kurelac I, Calvaruso MA, Capristo M, Lollini PL, Nanni P, Bergamini C, Nicoletti G, Giovanni CD, et al. Respiratory complex I is essential to induce a Warburg profile in mitochondria-defective tumor cells. Cancer Metab. 2013;1:11.
pubmed: 24280190
pmcid: 4178211
doi: 10.1186/2049-3002-1-11
Urra FA, Muñoz F, Lovy A, Cárdenas C. The mitochondrial complex(i)ty of cancer. Front Oncol. 2017;7:118.
pubmed: 28642839
pmcid: 5462917
doi: 10.3389/fonc.2017.00118
Schiliro C, Firestein BL. Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation. Cells. 2021;10:1056.
pubmed: 33946927
pmcid: 8146072
doi: 10.3390/cells10051056
LeBleu VS, O’Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 2014;16(992–1003):1001–15.
Davis RT, Blake K, Ma D, Gabra MBI, Hernandez GA, Phung AT, Yang Y, Maurer D, Lefebvre AEYT, Alshetaiwi H, et al. Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing. Nat Cell Biol. 2020;22:310–20.
pubmed: 32144411
doi: 10.1038/s41556-020-0477-0
De Luca A, Fiorillo M, Peiris-Pagès M, Ozsvari B, Smith DL, Sanchez-Alvarez R, Martinez-Outschoorn UE, Cappello AR, Pezzi V, Lisanti MP, Sotgia F. Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells. Oncotarget. 2015;6:14777–95.
pubmed: 26087310
pmcid: 4558115
doi: 10.18632/oncotarget.4401
Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O’Dwyer KM, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329–41.
pubmed: 23333149
pmcid: 3595363
doi: 10.1016/j.stem.2012.12.013
Peng M, Huang Y, Zhang L, Zhao X, Hou Y. Targeting mitochondrial oxidative phosphorylation eradicates acute myeloid leukemic stem cells. Front Oncol. 2022;12: 899502.
pubmed: 35574326
pmcid: 9100571
doi: 10.3389/fonc.2022.899502
Ye XQ, Li Q, Wang GH, Sun FF, Huang GJ, Bian XW, Yu SC, Qian GS. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer. 2011;129:820–31.
pubmed: 21520032
doi: 10.1002/ijc.25944
Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. 2016;114:1305–12.
pubmed: 27219018
pmcid: 4984474
doi: 10.1038/bjc.2016.152
Yap TA, Daver N, Mahendra M, Zhang J, Kamiya-Matsuoka C, Meric-Bernstam F, Kantarjian HM, Ravandi F, Collins ME, Francesco MED, et al. Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials. Nat Med. 2023;29:115–26.
pubmed: 36658425
doi: 10.1038/s41591-022-02103-8
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.
pubmed: 18445819
doi: 10.1093/jnci/djn123
Sin WC, Lim CL. Breast cancer stem cells-from origins to targeted therapy. Stem Cell Investig. 2017;4:96.
pubmed: 29270422
pmcid: 5723743
doi: 10.21037/sci.2017.11.03
Selvakumar P, Kumar S, Dimmock JR, Sharma RK. NMT1 (N-myristoyltransferase 1). Atlas Genet Cytogenet Oncol Haematol. 2011;15:570–5.
pubmed: 22977462
pmcid: 3439497
Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, Gill S, Harrington WF, Pantel S, Krill-Burger JM, et al. Defining a cancer dependency map. Cell. 2017;170:564-576.e516.
pubmed: 28753430
pmcid: 5667678
doi: 10.1016/j.cell.2017.06.010
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44: e71.
pubmed: 26704973
doi: 10.1093/nar/gkv1507
Cromwell CR, Sung K, Park J, Krysler AR, Jovel J, Kim SK, Hubbard BP. Incorporation of bridged nucleic acids into CRISPR RNAs improves Cas9 endonuclease specificity. Nat Commun. 2018;9:1448.
pubmed: 29654299
pmcid: 5899152
doi: 10.1038/s41467-018-03927-0
Cromwell CR, Hubbard BP. In vitro assays for comparing the specificity of first- and next-generation CRISPR/Cas9 systems. Methods Mol Biol. 2021;2162:215–32.
pubmed: 32926385
doi: 10.1007/978-1-0716-0687-2_12
Xia J, Wishart DS. MSEA: a web-based tool to identify biologically meaningful patterns in quantitative metabolomic data. Nucleic Acids Res. 2010;38:W71–7.
pubmed: 20457745
pmcid: 2896187
doi: 10.1093/nar/gkq329
Lampl T, Crum JA, Davis TA, Milligan C, Del Gaizo MV. Isolation and functional analysis of mitochondria from cultured cells and mouse tissue. J Vis Exp. 2015;97:52076.
Fernandez-Vizarra E, Zeviani M. Blue-native electrophoresis to study the OXPHOS complexes. In: Minczuk M, Rorbach J, editors. Mitochondrial gene expression: methods and protocols. New York, NY: Springer, US; 2021. p. 287–311.
doi: 10.1007/978-1-0716-0834-0_20
Yan LJ, Forster MJ. Resolving mitochondrial protein complexes using nongradient blue native polyacrylamide gel electrophoresis. Anal Biochem. 2009;389:143–9.
pubmed: 19348780
pmcid: 2795571
doi: 10.1016/j.ab.2009.03.043
Molina JR, Sun Y, Protopopova M, Gera S, Bandi M, Bristow C, McAfoos T, Morlacchi P, Ackroyd J, Agip AA, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018;24:1036–46.
pubmed: 29892070
doi: 10.1038/s41591-018-0052-4
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.
pubmed: 16199517
pmcid: 1239896
doi: 10.1073/pnas.0506580102
Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019;47:W199–205.
pubmed: 31114916
pmcid: 6602449
doi: 10.1093/nar/gkz401
Jourquin J, Duncan D, Shi Z, Zhang B. GLAD4U: deriving and prioritizing gene lists from PubMed literature. BMC Genomics. 2012;13(Suppl 8):S20.
pubmed: 23282288
pmcid: 3535723
doi: 10.1186/1471-2164-13-S8-S20
Newton Y, Novak AM, Swatloski T, McColl DC, Chopra S, Graim K, Weinstein AS, Baertsch R, Salama SR, Ellrott K, et al. TumorMap: exploring the molecular similarities of cancer samples in an interactive portal. Cancer Res. 2017;77:e111–4.
pubmed: 29092953
pmcid: 5751940
doi: 10.1158/0008-5472.CAN-17-0580
Baertling F, Sánchez-Caballero L, van den Brand MAM, Wintjes LT, Brink M, van den Brandt FA, Wilson C, Rodenburg RJT, Nijtmans LGJ. NDUFAF4 variants are associated with Leigh syndrome and cause a specific mitochondrial complex I assembly defect. Eur J Hum Genet. 2017;25:1273–7.
pubmed: 28853723
pmcid: 5643967
doi: 10.1038/ejhg.2017.133
Bartha Á, Győrffy B. TNMplot.com: a web tool for the comparison of gene expression in normal, tumor and metastatic tissues. Int J Mol Sci. 2021;22:2622.
pubmed: 33807717
pmcid: 7961455
doi: 10.3390/ijms22052622
Li Y, Ge D, Lu C. The SMART App: an interactive web application for comprehensive DNA methylation analysis and visualization. Epigenetics Chromatin. 2019;12:71.
pubmed: 31805986
pmcid: 6894252
doi: 10.1186/s13072-019-0316-3