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Celastrol Induces Apoptosis and Autophagy via the AKT/mTOR Signaling Pathway in the Pituitary ACTH-secreting Adenoma Cells

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Abstract

Objective

Pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma is a relatively intractable endocrine adenoma that can cause a range of severe metabolic disorders and pathological changes involving multiple systems. Previous studies have shown that celastrol has antitumor effects on a variety of tumor cells via the AKT/mTOR signaling. However, whether celastrol has pronounced antitumor effects on pituitary ACTH-secreting adenoma is unclear. This study aimed to identify a new effective therapeutic drug for pituitary ACTH-secreting adenoma.

Methods

Mouse pituitary ACTH-secreting adenoma cells (AtT20 cells) were used as an experimental model in vitro and to establish a xenograft tumor model in mice. Cells and animals were administered doses of celastrol at various levels. The effects of celastrol on cell viability, migration, apoptosis and autophagy were then examined. Finally, the potential involvement of AKT/mTOR signaling in celastrol’s mechanism was assessed.

Results

Celastrol inhibited the proliferation and migration of pituitary adenoma cells in a time- and concentration-dependent manner. It blocked AtT20 cells in the G0/G1 phase, and induced apoptosis and autophagy by downregulating the AKT/mTOR signaling pathway. Similar results were obtained in mice.

Conclusion

Celastrol exerts potent antitumor effects on ACTH-secreting adenoma by downregulating the AKT/mTOR signaling in vitro and in vivo.

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References

  1. Lau D, Rutledge C, Aghi MK. Cushing’s disease: current medical therapies and molecular insights guiding future therapies. Neurosurg Focus, 2015,38(2):E11

    Article  Google Scholar 

  2. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing’s syndrome. Lancet, 2015,386(9996):913–927

    Article  CAS  Google Scholar 

  3. Broersen LHA, Jha M, Biermasz NR, et al. Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary, 2018, 21(6):631–641

    Article  CAS  Google Scholar 

  4. Pivonello R, De Leo M, Cozzolino A, et al. The Treatment of Cushing’s Disease. Endocr Rev, 2015,36(4):385–486

    Article  CAS  Google Scholar 

  5. Wang CY, Bai XY, Wang CH. Traditional Chinese medicine: a treasured natural resource of anticancer drug research and development. Am J Chin Med, 2014, 42(3): 543–559

    Article  CAS  Google Scholar 

  6. Fan Y, Ma Z, Zhao L, et al. Anti-tumor activities and mechanisms of Traditional Chinese medicines formulas: A review. Biomed Pharmacother, 2020,132:110820.

    Article  CAS  Google Scholar 

  7. Wang SF, Wu MY, Cai CZ, et al. Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases. J Ethnopharmacol, 2016,194:861–876

    Article  CAS  Google Scholar 

  8. Wong VKW, Qiu C, Xu SW, et al. Ca(2+) signalling plays a role in celastrol-mediated suppression of synovial fibroblasts of rheumatoid arthritis patients and experimental arthritis in rats. Br J Pharmacol, 2019, 176(16):2922–2944

    Article  CAS  Google Scholar 

  9. Liu J, Lee J, Hernandez MAS, et al. Treatment of obesity with celastrol. Cell, 2015,161(5):999–1011

    Article  CAS  Google Scholar 

  10. Feng X, Guan D, Auen T, et al. IL1R1 is required for celastrol’s leptin-sensitization and antiobesity effects. Nat Med, 2019,25(4):575–582

    Article  CAS  Google Scholar 

  11. Peng X, Liang Y, Li J, et al. Preventive effects of “ovalbumin-conjugated celastrol-loaded nanomicelles” in a mouse model of ovalbumin-induced allergic airway inflammation. Eur J Pharm Sci, 2020,143:105172

    Article  CAS  Google Scholar 

  12. Chen X, Zhao Y, Luo W, et al. Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells. Theranostics, 2020,10(22):10290–10308

    Article  CAS  Google Scholar 

  13. Jiang Z, Cao Q, Dai G, et al. Celastrol inhibits colorectal cancer through TGF-β1/Smad signaling. Onco Targets Ther, 2019,12:509–518

    Article  CAS  Google Scholar 

  14. Zhao Y, Tan Y, Meng T, et al. Simultaneous targeting therapy for lung metastasis and breast tumor by blocking the NF-κB signaling pathway using Celastrol-loaded micelles. Drug Deliv, 2018,25(1):341–352

    Article  CAS  Google Scholar 

  15. Su Z, Yang Z, Xu Y, et al. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer, 2015, 14:48

    Article  Google Scholar 

  16. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol, 2020,17(7):395–417

    Article  Google Scholar 

  17. Grilo AL, Mantalaris A. Apoptosis: A mammalian cell bioprocessing perspective. Biotechnol Adv, 2019, 37(3): 459–475

    Article  CAS  Google Scholar 

  18. Wang RC, Wei Y, An Z, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science, 2012,338(6109):956–959

    Article  CAS  Google Scholar 

  19. Liu X, Zhao P, Wang X, et al. Celastrol mediates autophagy and apoptosis via the ROS/JNK and Akt/mTOR signaling pathways in glioma cells. J Exp Clin Cancer Res, 2019,38(1):184

    Article  Google Scholar 

  20. Zhu Y, Liu X, Zhao P, et al. Celastrol Suppresses Glioma Vasculogenic Mimicry Formation and Angiogenesis by Blocking the PI3K/Akt/mTOR Signaling Pathway. Front Pharmacol, 2020,11:25

    Article  CAS  Google Scholar 

  21. Li X, Zhu G, Yao X, et al. Celastrol induces ubiquitin-dependent degradation of mTOR in breast cancer cells. Onco Targets Ther, 2018,11:8977–8985

    Article  CAS  Google Scholar 

  22. Feng H, Cheng X, Kuang J, et al. Apatinib-induced protective autophagy and apoptosis through the AKT-mTOR pathway in anaplastic thyroid cancer. Cell Death Dis, 2018,9(10):1030

    Article  Google Scholar 

  23. Zhou J, Jiang YY, Chen H, et al. Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway. Cell Prolif, 2020, 53(2): e12739

    Article  Google Scholar 

  24. Dworakowska D, Wlodek E, Leontiou CA, et al. Activation of RAF/MEK/ERK and PI3K/AKT/mTOR pathways in pituitary adenomas and their effects on downstream effectors. Endocr Relat Cancer, 2009, 16(4): 1329–1338

    Article  CAS  Google Scholar 

  25. Song ZJ, Reitman ZJ, Ma ZY, et al. The genome-wide mutational landscape of pituitary adenomas. Cell Res, 2016,26(11):1255–1259

    Article  CAS  Google Scholar 

  26. Jin K, Ruan L, Pu J, et al. Metformin suppresses growth and adrenocorticotrophic hormone secretion in mouse pituitary corticotroph tumor AtT20 cells. Mol Cell Endocrinol, 2018,478:53–61

    Article  CAS  Google Scholar 

  27. Pivonello R, De Martino MC, De Leo, et al. Cushing’s disease: the burden of illness. Endocrine, 2017,56(1):10–18

    Article  CAS  Google Scholar 

  28. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg, 2017,126(2):404–417

    Article  Google Scholar 

  29. Lin FZ, Wang SC, Hsi YT, et al. Celastrol induces vincristine multidrug resistance oral cancer cell apoptosis by targeting JNK1/2 signaling pathway. Phytomedicine, 2019,54:1–8

    Article  CAS  Google Scholar 

  30. Li HY, Zhang J, Sun LL, et al. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study. Cell Death Dis, 2015,6(1):e1604

    Article  CAS  Google Scholar 

  31. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol, 2018,15(2):81–94

    Article  CAS  Google Scholar 

  32. Emmanuel R, Weinstein S, Landesman-Milo D, et al. eIF3c: a potential therapeutic target for cancer. Cancer Lett, 2013,336(1):158–166

    Article  CAS  Google Scholar 

  33. Peng B, Xu L, Cao F, et al. HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way. Mol Cancer, 2010,9:79

    Article  Google Scholar 

  34. Delbridge AR, Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ, 2015,22(7):1071–1080

    Article  CAS  Google Scholar 

  35. Kim B, Srivastava SK, Kim SH. Caspase-9 as a therapeutic target for treating cancer. Expert Opin Ther Targets, 2015,19(1):113–127

    Article  CAS  Google Scholar 

  36. Wu Y, Chen M, Jiang J. Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling. Mitochondrion, 2019,49:35–45

    Article  CAS  Google Scholar 

  37. Onorati AV, Dyczynski M, Ojha R, et al. Targeting autophagy in cancer. Cancer, 2018,124(16):3307–3318

    Article  Google Scholar 

  38. Jiang T, Chen X, Ren X, et al. Emerging role of autophagy in anti-tumor immunity: Implications for the modulation of immunotherapy resistance. Drug Resist Updat, 2021,56:100752

    Article  CAS  Google Scholar 

  39. Poillet-Perez L, White E. Role of tumor and host autophagy in cancer metabolism. Genes Dev, 2019, 33(11–12):610–619

    Article  CAS  Google Scholar 

  40. Shi YN, Liu LP, Deng CF, et al. Celastrol ameliorates vascular neointimal hyperplasia through Wnt5a-involved autophagy. Int J Biol Sci, 2021,17(10):2561–2575

    Article  CAS  Google Scholar 

  41. Wang L, Tang L, Yao C, et al. The Synergistic Effects of Celastrol in combination with Tamoxifen on Apoptosis and Autophagy in MCF-7 Cells. J Immunol Res, 2021, 2021:5532269

    Article  Google Scholar 

  42. Shi B, Ma M, Zheng Y, et al. mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury. J Cell Physiol, 2019,234(8):12562–12568

    Article  CAS  Google Scholar 

  43. Rodríguez-Hernández MA, González R, de la Rosa Á J, et al. Molecular characterization of autophagic and apoptotic signaling induced by sorafenib in liver cancer cells. J Cell Physiol, 2018,234(1):692–708

    Article  Google Scholar 

  44. Rahmani M, Nkwocha J, Hawkins E, et al. Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells. Cancer Res, 2018, 78(11): 3075–3086

    Article  CAS  Google Scholar 

  45. Chen S, Gu C, Xu C, et al. Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. J Neurochem, 2014,128(2):256–266

    Article  CAS  Google Scholar 

  46. Metselaar DS, Meel MH, Benedict B, et al. Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin. EBioMedicine, 2019,50:81–92

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Zhi Cai, Zhou-bin Tan, Kai Zhao & Ting Lei

  2. Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 211100, China

    Bin Qian

  3. Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China

    Jing Pang

Authors
  1. Zhi Cai
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  2. Bin Qian
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  3. Jing Pang
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  4. Zhou-bin Tan
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  5. Kai Zhao
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  6. Ting Lei
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Corresponding author

Correspondence to Ting Lei.

Ethics declarations

The authors declare that they have no competing interest.

Author Ting LEI is a member of the Editorial Board for Current Medical Science. The paper was handled by the other editor and has undergone rigorous peer review process. Author Ting LEI was not involved in the journal’s review of, or decision related to, this manuscript.

Additional information

This work was supported by the National Natural Science Youth Foundation of China (No. 81602204).

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Cai, Z., Qian, B., Pang, J. et al. Celastrol Induces Apoptosis and Autophagy via the AKT/mTOR Signaling Pathway in the Pituitary ACTH-secreting Adenoma Cells. CURR MED SCI 42, 387–396 (2022). https://doi.org/10.1007/s11596-022-2568-6

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  • DOI: https://doi.org/10.1007/s11596-022-2568-6

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