Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics

Acta Pharmacologica Sinica volume 44, pages 1701–1711 (2023)Cite this article

Abstract

Eriocalyxin B (EB), 17-hydroxy-jolkinolide B (HJB), parthenolide (PN), xanthatin (XT) and andrographolide (AG) are terpenoid natural products with a variety of promising antitumor activities, which commonly bear electrophilic groups (α,β–unsaturated carbonyl groups and/or epoxides) capable of covalently modifying protein cysteine residues. However, their direct targets and underlying molecular mechanisms are still largely unclear, which limits the development of these compounds. In this study, we integrated activity-based protein profiling (ABPP) and quantitative proteomics approach to systematically characterize the covalent targets of these natural products and their involved cellular pathways. We first demonstrated the anti-proliferation activities of these five compounds in triple-negative breast cancer cell MDA-MB-231. Tandem mass tag (TMT)-based quantitative proteomics showed all five compounds commonly affected the ubiquitin mediated proteolysis pathways. ABPP platform identified the preferentially modified targets of EB and PN, two natural products with high anti-proliferation activity. Biochemical experiments showed that PN inhibited the cell proliferation through targeting ubiquitin carboxyl-terminal hydrolase 10 (USP10). Together, this study uncovered the covalently modified targets of these natural products and potential molecular mechanisms of their antitumor activities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: EB, HJB, PN, XT, AG inhibited breast cancer cell proliferation.
Fig. 2: Characterization of global protein expression for five natural products.
Fig. 3: ABPP to map EB and PN targets in MDA-MB-231 cells.
Fig. 4: Biochemical validation of USP10 as a target of PN.

Similar content being viewed by others

Data availability

All mass spectrometry raw data have been deposited in the iProX Consortium under the Subproject ID: IPX0003210000 and PXD number: PXD036046.

References

  1. Butler MS. Natural products to drugs: natural product-derived compounds in clinical trials. Nat Prod Rep. 2008;25:475–516.

    Article  CAS  PubMed  Google Scholar 

  2. Baker DD, Chu M, Oza U, Rajgarhia V. The value of natural products to future pharmaceutical discovery. Nat Prod Rep. 2007;24:1225–44.

    Article  CAS  PubMed  Google Scholar 

  3. Nomura DK, Maimone TJ. Target identification of bioactive covalently acting natural products. Curr Top Microbiol Immunol. 2019;420:351–74.

    CAS  PubMed  Google Scholar 

  4. Kingston DGI. Modern natural products drug discovery and its relevance to biodiversity conservation. J Nat Prod. 2011;74:496–511.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang T, Hatcher JM, Teng M, Gray NS, Kostic M. Recent advances in selective and irreversible covalent ligand development and validation. Cell Chem Biol. 2019;26:1486–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lu Y, Chen B, Song JH, Zhen T, Wang BY, Li X, et al. Eriocalyxin B ameliorates experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells. Proc Natl Acad Sci USA. 2013;110:2258–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Leung CH, Grill SP, Lam W, Gao W, Sun HD, Cheng YC. Eriocalyxin B inhibits nuclear factor-κB activation by interfering with the binding of both p65 and p50 to the response element in a noncompetitive manner. Mol Pharmacol. 2006;70:1946.

    Article  CAS  PubMed  Google Scholar 

  8. Qin GW, Xu RS. Recent advances on bioactive natural products from Chinese medicinal plants. Med Res Rev. 1998;18:375–82.

    Article  CAS  PubMed  Google Scholar 

  9. Freund RRA, Gobrecht P, Fischer D, Arndt HD. Advances in chemistry and bioactivity of parthenolide. Nat Prod Rep. 2020;37:541–65.

    Article  CAS  PubMed  Google Scholar 

  10. Ghantous A, Sinjab A, Herceg Z, Darwiche N. Parthenolide: from plant shoots to cancer roots. Drug Discov Today. 2013;18:894–905.

    Article  CAS  PubMed  Google Scholar 

  11. Liu M, Xiao CQ, Sun MW, Tan MJ, Hu LH, Yu Q. Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases. J Cell Mol Med. 2019;23:4301–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ju A, Cho YC, Cho S. Methanol extracts of Xanthium sibiricum roots inhibit inflammatory responses via the inhibition of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in murine macrophages. J Ethnopharmacol. 2015;174:74–81.

    Article  PubMed  Google Scholar 

  13. Dai Y, Chen SR, Chai L, Zhao J, Wang Y, Wang Y. Overview of pharmacological activities of Andrographis paniculata and its major compound andrographolide. Crit Rev Food Sci Nutr. 2019;59:S17–29.

    Article  CAS  PubMed  Google Scholar 

  14. Li ZZ, Tan JP, Wang LL, Li QH. Andrographolide benefits rheumatoid arthritis via inhibiting MAPK pathways. Inflammation. 2017;40:1599–605.

    Article  CAS  PubMed  Google Scholar 

  15. Wen L, Xia N, Chen X, Li Y, Hong Y, Liu Y, et al. Activity of antibacterial, antiviral, anti-inflammatory in compounds andrographolide salt. Eur J Pharmacol. 2014;740:421–7.

    Article  CAS  PubMed  Google Scholar 

  16. Gersch M, Kreuzer J, Sieber SA. Electrophilic natural products and their biological targets. Nat Prod Rep. 2012;29:659–82.

    Article  CAS  PubMed  Google Scholar 

  17. Wang L, Zhao WL, Yan JS, Liu P, Sun HP, Zhou GB, et al. Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-κB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. Cell Death Differ. 2007;14:306–17.

    Article  PubMed  Google Scholar 

  18. Wang Y, Ma X, Yan S, Shen S, Zhu H, Gu Y, et al. 17-Hydroxy-jolkinolide B inhibits signal transducers and activators of transcription 3 signaling by covalently cross-linking Janus kinases and induces apoptosis of human cancer cells. Cancer Res. 2009;69:7302.

    Article  CAS  PubMed  Google Scholar 

  19. Wang Y, Shen S-Y, Liu L, Zhang X-D, Liu D-Y, Liu N, et al. Jolkinolide B inhibits proliferation or migration and promotes apoptosis of MCF-7 or BT-474 breast cancer cells by downregulating the PI3K-Akt pathway. J Ethnopharmacol. 2022;282:114581.

    Article  CAS  PubMed  Google Scholar 

  20. Sohma I, Fujiwara Y, Sugita Y, Yoshioka A, Shirakawa M, Moon JH, et al. Parthenolide, an NF-κB inhibitor, suppresses tumor growth and enhances response to chemotherapy in gastric cancer. Cancer Genom Proteom. 2011;8:39–47.

    CAS  Google Scholar 

  21. Mathema VB, Koh YS, Thakuri BC, Sillanpää M. Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities. Inflammation. 2012;35:560–5.

    Article  CAS  PubMed  Google Scholar 

  22. Liu M, Xiao C, Sun M, Tan M, Hu L, Yu Q. Parthenolide inhibits STAT3 signaling by covalently targeting Janus kinases. Molecules. 2018;23:1478.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Berdan CA, Ho R, Lehtola HS, To M, Hu X, Huffman TR, et al. Parthenolide covalently targets and inhibits focal adhesion kinase in breast cancer cells. Cell Chem Biol. 2019;26:1027–35.e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shi TL, Zhang L, Cheng QY, Yu JS, Liu J, Shen YJ, et al. Xanthatin induces apoptosis by activating endoplasmic reticulum stress in hepatoma cells. Eur J Pharmacol. 2019;843:1–11.

    Article  CAS  PubMed  Google Scholar 

  25. Li L, Liu P, Xie Y, Liu Y, Chen Z, Geng Y, et al. Xanthatin inhibits human colon cancer cells progression via mTOR signaling mediated energy metabolism alteration. Drug Dev Res. 2022;83:119–30.

    Article  CAS  PubMed  Google Scholar 

  26. Tohkayomatee R, Reabroi S, Tungmunnithum D, Parichatikanond W, Pinthong D. Andrographolide exhibits anticancer activity against breast cancer cells (MCF-7 and MDA-MB-231 cells) through suppressing cell proliferation and inducing cell apoptosis via inactivation of ER-α receptor and PI3K/AKT/mTOR signaling. Molecules. 2022;27:3544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chou YJ, Lin CC, Hsu YC, Syu JL, Tseng LM, Chiu JH, et al. Andrographolide suppresses the malignancy of triple-negative breast cancer by reducing THOC1-promoted cancer stem cell characteristics. Biochem Pharmacol. 2022;206:115327.

    Article  CAS  PubMed  Google Scholar 

  28. Cravatt BF, Simon GM, Yates JR 3rd. The biological impact of mass-spectrometry-based proteomics. Nature. 2007;450:991–1000.

    Article  CAS  PubMed  Google Scholar 

  29. Federspiel JD, Codreanu SG, Goyal S, Albertolle ME, Lowe E, Teague J, et al. Specificity of protein covalent modification by the electrophilic proteasome inhibitor Carfilzomib in human cells. Mol Cell Proteom. 2016;15:3233.

    Article  CAS  Google Scholar 

  30. Patterson SD, Aebersold RH. Proteomics: the first decade and beyond. Nat Genet. 2003;33:311–23.

    Article  CAS  PubMed  Google Scholar 

  31. Domon B, Aebersold R. Mass spectrometry and protein analysis. Science. 2006;312:212–7.

    Article  CAS  PubMed  Google Scholar 

  32. Barglow KT, Cravatt BF. Activity-based protein profiling for the functional annotation of enzymes. Nat Methods. 2007;4:822–7.

    Article  CAS  PubMed  Google Scholar 

  33. Niphakis MJ, Cravatt BF. Enzyme inhibitor discovery by activity-based protein profiling. Annu Rev Biochem. 2014;83:341–77.

    Article  CAS  PubMed  Google Scholar 

  34. Wang C, Weerapana E, Blewett MM, Cravatt BF. A chemoproteomic platform to quantitatively map targets of lipid-derived electrophiles. Nat Methods. 2014;11:79–85.

    Article  PubMed  Google Scholar 

  35. Lanning BR, Whitby LR, Dix MM, Douhan J, Gilbert AM, Hett EC, et al. A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nat Chem Biol. 2014;10:760–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, et al. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun. 2015;6:10111.

    Article  CAS  PubMed  Google Scholar 

  37. Niessen S, Dix MM, Barbas S, Potter ZE, Lu S, Brodsky O, et al. Proteome-wide map of targets of T790M-EGFR-directed covalent inhibitors. Cell Chem Biol. 2017;24:1388–400.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Deng X, Weerapana E, Ulanovskaya O, Sun F, Liang H, Ji Q, et al. Proteome-wide quantification and characterization of oxidation-sensitive cysteines in pathogenic bacteria. Cell Host Microbe. 2013;13:358–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Backus KM, Correia BE, Lum KM, Forli S, Horning BD, González-Páez GE, et al. Proteome-wide covalent ligand discovery in native biological systems. Nature. 2016;534:570–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fonović M, Verhelst SH, Sorum MT, Bogyo M. Proteomics evaluation of chemically cleavable activity-based probes. Mol Cell Proteom. 2007;6:1761–70.

    Article  Google Scholar 

  41. Tian C, Sun R, Liu K, Fu L, Liu X, Zhou W, et al. Multiplexed thiol reactivity profiling for target discovery of electrophilic natural products. Cell Chem Biol. 2017;24:1416–27.e5.

    Article  CAS  PubMed  Google Scholar 

  42. Savitski MM, Mathieson T, Zinn N, Sweetman G, Doce C, Becher I, et al. Measuring and managing ratio compression for accurate iTRAQ/TMT quantification. J Proteome Res. 2013;12:3586–98.

    Article  CAS  PubMed  Google Scholar 

  43. Ow SY, Salim M, Noirel J, Evans C, Rehman I, Wright PC. iTRAQ underestimation in simple and complex mixtures: “the good, the bad and the ugly”. J Proteome Res. 2009;8:5347–55.

    Article  CAS  PubMed  Google Scholar 

  44. Ow SY, Salim M, Noirel J, Evans C, Wright PC. Minimising iTRAQ ratio compression through understanding LC-MS elution dependence and high-resolution HILIC fractionation. Proteomics. 2011;11:2341–6.

    Article  CAS  PubMed  Google Scholar 

  45. Verhelst SH, Fonović M, Bogyo M. A mild chemically cleavable linker system for functional proteomic applications. Angew Chem Int Ed Engl. 2007;46:1284–6.

    Article  CAS  PubMed  Google Scholar 

  46. Xu FW, Xiao CQ, Lv X, Lei M, Hu LH. Two new dimmeric xanthanolides isolated from Xanthiurn mogolium Kitag plant. Tetrahedron Lett. 2017;58:1312–5.

    Article  CAS  Google Scholar 

  47. Che CT, Zhou TX, Ma QG, Qin GW, Williams ID, Wu HM, et al. Diterpenes and aromatic compounds from Euphorbia fischeriana. Phytochemistry. 1999;52:117–21.

    Article  CAS  Google Scholar 

  48. Xu G, Wang J, Wu Z, Qian L, Dai L, Wan X, et al. SAHA regulates histone acetylation, butyrylation, and protein expression in neuroblastoma. J Proteome Res. 2014;13:4211–9.

    Article  CAS  PubMed  Google Scholar 

  49. Weerapana E, Wang C, Simon GM, Richter F, Khare S, Dillon MB, et al. Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature. 2010;468:790–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dayon L, Hainard A, Licker V, Turck N, Kuhn K, Hochstrasser DF, et al. Relative quantification of proteins in human cerebrospinal fluids by MS/MS using 6-plex isobaric tags. Anal Chem. 2008;80:2921–31.

    Article  CAS  PubMed  Google Scholar 

  51. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.

    Article  CAS  PubMed  Google Scholar 

  52. Chen Y, Kwon SW, Kim SC, Zhao Y. Integrated approach for manual evaluation of peptides identified by searching protein sequence databases with tandem mass spectra. J Proteome Res. 2005;4:998–1005.

    Article  CAS  PubMed  Google Scholar 

  53. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, et al. STRING 8-a global view on proteins and their functional interactions in 630 organisms. Nucleic Acids Res. 2009;37:D412–6.

    Article  CAS  PubMed  Google Scholar 

  55. Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4:2.

    Article  Google Scholar 

  56. Wang J, Vasaikar S, Shi Z, Greer M, Zhang B. WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit. Nucleic Acids Res. 2017;45:W130–w7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang Y, Wang ZH, Liu Y, Chen Y, Sun N, Gucek M, et al. PINK1 inhibits local protein synthesis to limit transmission of deleterious mitochondrial DNA mutations. Mol Cell. 2019;73:1127.e5.

    Article  Google Scholar 

  58. Hou S, Qu D, Li Y, Zhu B, Liang D, Wei X, et al. XAB2 depletion induces intron retention in POLR2A to impair global transcription and promote cellular senescence. Nucleic Acids Res. 2019;47:8239–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kapanidou M, Curtis NL, Bolanos-Garcia VM. Cdc20: at the crossroads between chromosome segregation and mitotic exit. Trends Biochem Sci. 2017;42:193–205.

    Article  CAS  PubMed  Google Scholar 

  60. Wang L, Zhang J, Wan L, Zhou X, Wang Z, Wei W. Targeting Cdc20 as a novel cancer therapeutic strategy. Pharmacol Ther. 2015;151:141–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li X, Kong L, Yang Q, Duan A, Ju X, Cai B, et al. Parthenolide inhibits ubiquitin-specific peptidase 7 (USP7), Wnt signaling, and colorectal cancer cell growth. J Biol Chem. 2020;295:3576–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gopal YN, Chanchorn E, Van Dyke MW. Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions. Mol Cancer Ther. 2009;8:552–62.

    Article  CAS  PubMed  Google Scholar 

  63. Li Z, Liu K, Xu P, Yang J. Benchmarking cleavable biotin tags for peptide-centric chemoproteomics. J Proteome Res. 2022;21:1349–58.

    Article  CAS  PubMed  Google Scholar 

  64. Martin BR, Wang C, Adibekian A, Tully SE, Cravatt BF. Global profiling of dynamic protein palmitoylation. Nat Methods. 2011;9:84–9.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature. 2019;568:511–6.

    Article  CAS  PubMed  Google Scholar 

  66. Menendez JA, Lupu R. Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets. 2017;21:1001–16.

    Article  CAS  PubMed  Google Scholar 

  67. Ye F, Huang J, Wang H, Luo C, Zhao K. Targeting epigenetic machinery: emerging novel allosteric inhibitors. Pharmacol Ther. 2019;204:107406.

    Article  CAS  PubMed  Google Scholar 

  68. Maennling AE, Tur MK, Niebert M, Klockenbring T, Zeppernick F, Gattenlöhner S, et al. Molecular targeting therapy against EGFR family in breast cancer: progress and future potentials. Cancers. 2019;11:1826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang S, Ju X, Yang Q, Zhu Y, Fan D, Su G, et al. USP47 maintains the stemness of colorectal cancer cells and is inhibited by parthenolide. Biochem Biophys Res Commun. 2021;562:21–8.

    Article  CAS  PubMed  Google Scholar 

  70. Bhattacharya U, Neizer-Ashun F, Mukherjee P, Bhattacharya R. When the chains do not break: the role of USP10 in physiology and pathology. Cell Death Dis. 2020;11:1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Takayama KI, Suzuki T, Fujimura T, Takahashi S, Inoue S. Association of USP10 with G3BP2 inhibits p53 signaling and contributes to poor outcome in prostate cancer. Mol Cancer Res. 2018;16:846–56.

    Article  CAS  PubMed  Google Scholar 

  72. Grunda JM, Nabors LB, Palmer CA, Chhieng DC, Steg A, Mikkelsen T, et al. Increased expression of thymidylate synthetase (TS), ubiquitin specific protease 10 (USP10) and survivin is associated with poor survival in glioblastoma multiforme (GBM). J Neurooncol. 2006;80:261–74.

    Article  CAS  PubMed  Google Scholar 

  73. Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49:1779–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yuan J, Luo K, Zhang L, Cheville JC, Lou Z. USP10 regulates p53 localization and stability by deubiquitinating p53. Cell. 2010;140:384–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Borovski T, Vellinga TT, Laoukili J, Santo EE, Fatrai S, van Schelven S, et al. Inhibition of RAF1 kinase activity restores apicobasal polarity and impairs tumour growth in human colorectal cancer. Gut. 2017;66:1106–15.

    Article  CAS  PubMed  Google Scholar 

  76. Chen J, Fujii K, Zhang L, Roberts T, Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA. 2001;98:7783–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang M, Hu Y, Stearns ME. RPS2: a novel therapeutic target in prostate cancer. J Exp Clin Cancer Res. 2009;28:6.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wang L, Liang Y, Li P, Liang Q, Sun H, Xu D, et al. Oncogenic activities of UBE2S mediated by VHL/HIF-1α/STAT3 signal via the ubiquitin-proteasome system In PDAC. Onco Targets Ther. 2019;12:9767–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang W, Cao L, Sun Z, Xu J, Tang L, Chen W, et al. Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation. Cell Cycle. 2016;15:1344–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. García-Piñeres AJ, Castro V, Mora G, Schmidt TJ, Strunck E, Pahl HL, et al. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem. 2001;276:39713–20.

    Article  PubMed  Google Scholar 

  81. Liu Z, Liu S, Xie Z, Pavlovicz RE, Wu J, Chen P, et al. Modulation of DNA methylation by a sesquiterpene lactone parthenolide. J Pharmacol Exp Ther. 2009;329:505–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Duhamel S, Goyette MA, Thibault MP, Filion D, Gaboury L, Côté JF. The E3 ubiquitin ligase HectD1 suppresses EMT and metastasis by targeting the +TIP ACF7 for degradation. Cell Rep. 2018;22:1016–30.

    Article  CAS  PubMed  Google Scholar 

  83. Wang X, Ye M, Wu M, Fang H, Xiao B, Xie L, et al. RNF213 suppresses carcinogenesis in glioblastoma by affecting MAPK/JNK signaling pathway. Clin Transl Oncol. 2020;22:1506–16.

    Article  CAS  PubMed  Google Scholar 

  84. Banh RS, Iorio C, Marcotte R, Xu Y, Cojocari D, Rahman AA, et al. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat Cell Biol. 2016;18:803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Piccolis M, Bond LM, Kampmann M, Pulimeno P, Chitraju C, Jayson CB, et al. Probing the global cellular responses to lipotoxicity caused by saturated fatty acids. Mol Cell. 2019;74:32–44.e8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Li Y, Huang B, Yang H, Kan S, Yao Y, Liu X, et al. Latexin deficiency in mice up-regulates inflammation and aggravates colitis through HECTD1/Rps3/NF-κB pathway. Sci Rep. 2020;10:1–14.

    Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (2020YFE0202200), the National Natural Science Foundation of China (32071432, 21907100, 22225702), the Program of Shanghai Academic Research Leader (22XD1420900), the Science and Technology Commission of Shanghai Municipality (19JC1416300), the Natural Science Foundation of China for Innovation Research Group (81821005), the Shanghai Sailing Program (21YF1456000), the open fund of state key laboratory of Pharmaceutical Biotechnology, Nanjing University, China (KF-202201), and the National Key R&D Program of China (2018YFC1705500).

Author information

Author notes

  1. These authors contributed equally: Wen-si Zhao, Kai-feng Chen

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen-si Zhao, Kai-feng Chen, Man Liu, Xing-long Jia, Yu-qi Huang, Bing-bing Hao, Hao Hu, Qiang Yu & Min-jia Tan

  2. University of Chinese Academy of Sciences, Beijing, 101408, China

    Wen-si Zhao, Kai-feng Chen, Yu-qi Huang & Min-jia Tan

  3. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Wen-si Zhao, Kai-feng Chen & Min-jia Tan

  4. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Xing-long Jia & Xiao-yan Shen

  5. Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China

    Min-jia Tan

Authors
  1. Wen-si Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai-feng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Man Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xing-long Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-qi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bing-bing Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hao Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao-yan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qiang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Min-jia Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MJT designed and supervised this study. WSZ performed the drug sensitivity experiments in cancer cell lines, TMT-based quantitative proteomics analysis, activity-based protein profiling (ABPP) and bioinformatics analysis. ML and QY provided the compounds and participated in part of the designing and performing of the experiments. KFC and XLJ performed the biological validation experiments. YQH performed the bioinformatics analysis. WSZ wrote the manuscript, and KFC, BBH, HH, XYS, and MJT revised it.

Corresponding author

Correspondence to Min-jia Tan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Ws., Chen, Kf., Liu, M. et al. Investigation of targets and anticancer mechanisms of covalently acting natural products by functional proteomics. Acta Pharmacol Sin 44, 1701–1711 (2023). https://doi.org/10.1038/s41401-023-01072-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01072-z

Keywords

This article is cited by

Search

Advanced search

Quick links