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Cited by 19Cancer, Hypoxia, and MetabolismCancer, Lipids, and MetabolismMetabolism, Diabetes, and Cancer

Itraconazole inhibits tumor growth via CEBPB‐mediated glycolysis in colorectal cancer

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Zhang, Yong, Li, Lu, Chu, Feifei, Wu, Huili, Xiao, Xingguo, Ye, Jianping, Li, Kunkun·2024·Cancer Science
DOI 10.1111/cas.16082PMC PMC11007002
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Abstract

Advanced colorectal cancer (CRC) is characterized by a high recurrence and metastasis rate, which is the primary cause of patient mortality. Unfortunately, effective anti‐cancer drugs for CRC are still lacking in clinical practice. We screened FDA‐approved drugs by utilizing targeted organoid sequencing data and found that the antifungal drug itraconazole had a potential therapeutic effect on CRC tumors. However, the effect and mechanism of itraconazole on CRC tumors have not been investigated. A cell line‐derived xenograft model in tumor‐bearing mice was established and single‐cell RNA sequencing was performed on tumor samples from four mice with or without itraconazole treatment. The proportion of cell populations and gene expression profiles was significantly different between the two groups. We found that itraconazole could inhibit tumor growth and glycolysis. We revealed that CEBPB was a new target for itraconazole, and that silencing CEBPB could repress CRC glycolysis and tumor growth by inhibiting ENO1 expression. Clinical analysis showed that CEBPB expression was obviously elevated in CRC patients, and was associated with poor survival. In summary, itraconazole treatment remodeled cell composition and gene expression profiles. Itraconazole inhibited cell glycolysis and tumor growth via the CEBPB–ENO1 axis. In this study, we illustrate a new energy metabolism mechanism for itraconazole on tumor growth in CRC that will provide a theoretical basis for CRC targeting/combination therapy.

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  1. [1]Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Can J Clinic. 2021; 71(3): 209‐ 249. 33538338
  2. [2]Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021; 325(7): 669‐ 685. 33591350
  3. [3]Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J, Cervantes A. Clinical management of metastatic colorectal cancer in the era of precision medicine. CA: Can J Clinic. 2022; 72(4): 372‐ 401. 35472088
  4. [5]Deng H, Huang L, Liao Z, Liu M, Li Q, Xu R. Itraconazole inhibits the hedgehog signaling pathway thereby inducing autophagy‐mediated apoptosis of colon cancer cells. Cell Death Dis. 2020; 11(7): 539. 32681018 PMC7367825
  5. [6]Shen PW, Chou YM, Li CL, et al. Itraconazole improves survival outcomes in patients with colon cancer by inducing autophagic cell death and inhibiting transketolase expression. Oncol Lett. 2021; 22(5): 768. 34589147 PMC8442143
  6. [8]Buczacki SJA, Popova S, Biggs E, et al. Itraconazole targets cell cycle heterogeneity in colorectal cancer. J Exp Med. 2018; 215(7): 1891‐ 1912. 29853607 PMC6028508
  7. [9]Martinez‐Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021; 21(10): 669‐ 680. 34272515
  8. [10]DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020; 2(2): 127‐ 129. 32694689
  9. [11]Wang G, Wang JJ, Yin PH, et al. New strategies for targeting glucose metabolism‐mediated acidosis for colorectal cancer therapy. J Cell Physiol. 2018; 234(1): 348‐ 368. 30069931
  10. [12]Hong J, Guo F, Lu SY, et al. F. Nucleatum targets lncRNA ENO1‐IT1 to promote glycolysis and oncogenesis in colorectal cancer. Gut. 2021; 70(11): 2123‐ 2137. 33318144
  11. [13]Huang CK, Sun Y, Lv L, Ping Y. ENO1 and cancer. Mol Ther–Oncol. 2022; 24: 288‐ 298. PMC8987341 35434271
  12. [14]Lin YH, Satani N, Hammoudi N, et al. An enolase inhibitor for the targeted treatment of ENO1‐deleted cancers. Nat Metab. 2020; 2(12): 1413‐ 1426. 33230295 PMC7744354
  13. [15]Zhou Q, Sun X, Pasquier N, et al. Cell‐penetrating CEBPB and CEBPD leucine zipper decoys as broadly acting anti‐cancer agents. Cancers. 2021; 13(10): 2504. 34065488 PMC8161188
  14. [16]Wang Z, Pang J, Wang L, Dong Q, Jin D. CEBPB regulates the bile acid receptor FXR to accelerate colon cancer progression by modulating aerobic glycolysis. J Clin Lab Anal. 2022; 36(11): e24703. 36129029 PMC9701896
  15. [17]Weinstein JN, Collisson EA, Mills GB, et al. The cancer genome atlas pan‐cancer analysis project. Nat Genet. 2013; 45(10): 1113‐ 1120. 24071849 PMC3919969
  16. [18]Wu P, Heins ZJ, Muller JT, et al. Integration and analysis of CPTAC proteomics data in the context of cancer genomics in the cBioPortal. Mol Cell Proteomics. 2019; 18(9): 1893‐ 1898. 31308250 PMC6731080
  17. [20]Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst. 2015; 1(6): 417‐ 425. 26771021 PMC4707969
  18. [21]Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovations. 2021; 2(3): 100141. PMC8454663 34557778
  19. [22]Norkin M, Ordóñez‐Morán P, Huelsken J. High‐content, targeted RNA‐seq screening in organoids for drug discovery in colorectal cancer. Cell Rep. 2021; 35(3): 109026. 33882314
  20. [24]Wu Y, Yang S, Ma J, et al. Spatiotemporal immune landscape of colorectal cancer liver metastasis at single‐cell level. Cancer Discov. 2022; 12(1): 134‐ 153. 34417225
  21. [25]Ge T, Yang J, Zhou S, Wang Y, Li Y, Tong X. The role of the pentose phosphate pathway in diabetes and cancer. Front Endocrinol. 2020; 11: 365. PMC7296058 32582032
  22. [26]Bensard CL, Wisidagama DR, Olson KA, et al. Regulation of tumor initiation by the mitochondrial pyruvate carrier. Cell Metab. 2020; 31(2): 284‐ 300. 31813825 PMC7004878
  23. [27]Aibar S, González‐Blas CB, Moerman T, et al. SCENIC: single‐cell regulatory network inference and clustering. Nat Methods. 2017; 14(11): 1083‐ 1086. 28991892 PMC5937676
  24. [28]Wang D, Yang L, Yu W, et al. Colorectal cancer cell‐derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF‐κB signaling. J Immunother Cancer. 2019; 7(1): 215. 31395078 PMC6688336
  25. [29]Sun L, Fu BB, Liu DG. Systemic delivery of full‐length C/EBP beta/liposome complex suppresses growth of human colon cancer in nude mice. Cell Res. 2005; 15(10): 770‐ 776. 16246266
  26. [30]Hu T, Liu H, Liang Z, et al. Tumor‐intrinsic CD47 signal regulates glycolysis and promotes colorectal cancer cell growth and metastasis. Theranostics. 2020; 10(9): 4056‐ 4072. 32226539 PMC7086360
  27. [32]Frey T, De Maio A. The antifungal agent itraconazole induces the accumulation of high mannose glycoproteins in macrophages. J Biol Chem. 2009; 284(25): 16882‐ 16890. 19414590 PMC2719324
  28. [33]Hara M, Nagasaki T, Shiga K, Takeyama H. Suppression of cancer‐associated fibroblasts and endothelial cells by Itraconazole in bevacizumab‐resistant gastrointestinal cancer. Anticancer Res. 2016; 36(1): 169‐ 177. 26722041
  29. [34]Qi J, Cheng W, Gao Z, et al. Itraconazole inhibits endothelial cell migration by disrupting inositol pyrophosphate‐dependent focal adhesion dynamics and cytoskeletal remodeling. Biomed Pharmacother. 2023; 161: 114449. 36857911 PMC7614367
  30. [35]Head SA, Shi W, Zhao L, et al. Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci U S A. 2015; 112(52): E7276‐ E7285. 26655341 PMC4703001
  31. [36]Steel HC, Tintinger GR, Theron AJ, Anderson R. Itraconazole‐mediated inhibition of calcium entry into platelet‐activating factor‐stimulated human neutrophils is due to interference with production of leukotriene B4. Clin Exp Immunol. 2007; 150(1): 144‐ 150. 17683509 PMC2219290
  32. [37]Steel HC, Anderson R. Itraconazole antagonizes store‐operated influx of calcium into chemoattractant‐activated human neutrophils. Clin Exp Immunol. 2004; 136(2): 255‐ 261. 15086388 PMC1809014
  33. [38]Du W, Jiang P, Mancuso A, et al. TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol. 2013; 15(8): 991‐ 1000. 23811687 PMC3733810
  34. [39]Li Y, Yao CF, Xu FJ, et al. APC/C(CDH1) synchronizes ribose‐5‐phosphate levels and DNA synthesis to cell cycle progression. Nat Commun. 2019; 10(1): 2502. 31175280 PMC6555833
  35. [40]Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of cancer. Annu Rev Physiol. 2020; 82: 103‐ 126. 31730395
  36. [41]Tanner LB, Goglia AG, Wei MH, et al. Four key steps control glycolytic flux in mammalian cells. Cell Syst. 2018; 7(1): 49‐ 62. 29960885 PMC6062487
  37. [42]Nenkov M, Ma Y, Gaßler N, Chen Y. Metabolic reprogramming of colorectal cancer cells and the microenvironment: implication for therapy. Int J Mol Sci. 2021; 22(12): 6262. 34200820 PMC8230539
  38. [44]Hegde S, Leader AM, Merad M. MDSC: markers, development, states, and unaddressed complexity. Immunity. 2021; 54(5): 875‐ 884. 33979585 PMC8709560
  39. [45]Fultang N, Li X, Li T, Chen YH. Myeloid‐derived suppressor cell differentiation in cancer: transcriptional regulators and Enhanceosome‐mediated mechanisms. Front Immunol. 2020; 11: 619253. 33519825 PMC7840597
  40. [46]Boutilier AJ, Elsawa SF. Macrophage polarization states in the tumor microenvironment. Int J Mol Sci. 2021; 22(13): 6995. 34209703 PMC8268869
  41. [47]Qiu Y, Chen T, Hu R, et al. Next frontier in tumor immunotherapy: macrophage‐mediated immune evasion. Biomarker Res. 2021; 9(1): 72. PMC8501632 34625124
  42. [48]Li C, Xu MM, Wang K, Adler AJ, Vella AT, Zhou B. Macrophage polarization and meta‐inflammation. Transl Res. 2018; 191: 29‐ 44. 29154757 PMC5776711
  43. [49]Mohamed AW, Elbassiouny M, Elkhodary DA, Shawki MA, Saad AS. The effect of itraconazole on the clinical outcomes of patients with advanced non‐small cell lung cancer receiving platinum‐based chemotherapy: a randomized controlled study. Med Oncol. 2021; 38(3): 23. 33559053
  44. [50]Wang X, Wei S, Zhao Y, et al. Anti‐proliferation of breast cancer cells with itraconazole: hedgehog pathway inhibition induces apoptosis and autophagic cell death. Cancer Lett. 2017; 385: 128‐ 136. 27810405
  45. [52]Lin MC, Chuang YT, Wu HY, et al. Targeting tumor O‐glycosylation modulates cancer‐immune‐cell crosstalk and enhances anti‐PD‐1 immunotherapy in head and neck cancer. Mol Oncol. 2023. PMC10850803 37452653

Cited by

Sorted by citations

Authors
Zhang, Y., Li, L., Chu, F., Wu, H., Xiao, X., Ye, J., & Li, K.
Affiliations
Zhengzhou University (CN)
Corresponding author
  • Ye, Jianping
  • Li, Kunkun
ORCID
Venue
Cancer Science
Publisher
Wiley
Published
2024-01-26
Volume
115
Issue
4
Pages
1154-1169
ISSN
  • 1347-9032 (ISSN-L)
  • 1349-7006
DOI
10.1111/cas.16082
PMC
PMC11007002
OpenAlex
W4391270220
Cited by
19
References
7
Citations by year
2026: 6 · 2025: 8 · 2024: 5
FWCI
3.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Science (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
itraconazole, colorectal cancer, CEBPB, alpha-enolase, glycolysis, tumor energy metabolism, antifungal drug repurposing, tumor growth inhibition, tumor cell composition, single-cell RNA sequencing, cell of origin, prognostic factors
MeSH terms
Animals, Disease Models, Animal, Glycolysis, Humans, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Itraconazole, CCAAT-Enhancer-Binding Protein-beta, Cell Line, Tumor, Cell Proliferation, Mice

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