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Periplogenin suppresses the growth of esophageal squamous cell carcinoma in vitro and in vivo by targeting STAT3

Oncogene volume 40, pages 3942–3958 (2021)Cite this article

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Abstract

The mortality rate of esophageal squamous cell carcinoma (ESCC) is higher than that of other cancers worldwide owing to a lack of therapeutic targets and related drugs. This study aimed to find new drugs by targeting an efficacious therapeutic target in ESCC patients. Signal transducer and activator of transcription 3 (STAT3) is hyperactive in ESCC. Herein, we identified a novel STAT3 inhibitor, periplogenin, which strongly inhibited phosphorylation of STAT3 at Tyr705. Docking models and pull-down assays revealed that periplogenin bound directly and specifically to STAT3, leading to significant suppression of subsequent dimerization, nuclear import, and transcription activities. In addition, STAT3 knockdown cell lines were insensitive to periplogenin, whereas in contrast, STAT3-overexpressing cells were more sensitive to periplogenin, indicating that STAT3 was a target of periplogenin. Intraperitoneally administered periplogenin exhibited efficacious therapeutic effects in ESCC patient-derived xenograft models and dramatically impaired the phosphorylation of STAT3 and expression levels of STAT3-mediated downstream genes. Thus, our study demonstrated that periplogenin acted as a new STAT3 inhibitor, suppressing the growth of ESCC in vitro and in vivo, providing a basis for its potential application in ESCC treatment and prevention.

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Fig. 1: Periplogenin inhibits the ESCC cell growth.
Fig. 2: Periplogenin directly binds to STAT3 and inhibits phosphorylation of STAT3 at Tyr705.
Fig. 3: STAT3 is a potential therapeutic target in ESCC.
Fig. 4: Periplogenin inhibits IL-6-induced dimerization, nuclear import, and transcriptional activity of STAT3 and its related pathway.
Fig. 5: Periplogenin inhibits ESCC cell growth in a STAT3-dependent manner.
Fig. 6: Periplogenin inhibits ESCC growth in vivo.
Fig. 7: Periplogenin significantly inhibits ESCC growth, reducing the levels of p-STAT3 Tyr705 compared with other STAT3 inhibitors.

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References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer J clinicians. 2018;68:394–424.

    Google Scholar 

  2. Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 2014;509:91–95.

    Article  CAS  PubMed  Google Scholar 

  3. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.

    Article  PubMed  Google Scholar 

  4. Smyth EC, Lagergren J, Fitzgerald RC, Lordick F, Shah MA, Lagergren P, et al. Oesophageal cancer. Nat Rev Dis Prim. 2017;3:17048.

    Article  PubMed  Google Scholar 

  5. Khazaei S, Soheylizad M, Veisani Y, Rezaeian S, Biderafsh A, et al. Global inequality in the incidence and mortality rates of esophageal cancer: a country-level analysis. Int J Cancer Manag. 2018;11:e10059.

  6. Pan R, Zhu M, Yu C, Lv J, Guo Y, Bian Z, et al. Cancer incidence and mortality: a cohort study in China, 2008-2013. Int J Cancer. 2017;141:1315–23.

    Article  CAS  PubMed  Google Scholar 

  7. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA: a cancer J clinicians. 2016;66:115–32.

    Google Scholar 

  8. van Rossum PSN, Mohammad NH, Vleggaar FP, van Hillegersberg R. Treatment for unresectable or metastatic oesophageal cancer: current evidence and trends. Nat Rev Gastroenterol & Hepatol. 2018;15:235–49.

  9. Okines A, Sharma B, Cunningham D. Perioperative management of esophageal cancer. Nat Rev Clin Oncol. 2010;7:231–8.

    Article  CAS  PubMed  Google Scholar 

  10. Kato K, Muro K, Ando N, Nishimaki T, Ohtsu A, Aogi K, et al. A phase II study of nedaplatin and 5-fluorouracil in metastatic squamous cell carcinoma of the esophagus: The Japan Clinical Oncology Group (JCOG) Trial (JCOG 9905-DI). Esophagus. 2014;11:183–8.

    Article  CAS  Google Scholar 

  11. Huynh J, Chand A, Gough D, Ernst M. Therapeutically exploiting STAT3 activity in cancer - using tissue repair as a road map. Nat Rev Cancer. 2019;19:82–96.

  12. Yu H. STATs in cancer inflammantation and immunity: a leading role for STAT3. Natrevcancer. 2009;9:798–809.

    CAS  Google Scholar 

  13. Yu H, Jove R. The STATs of cancer — new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.

    Article  CAS  PubMed  Google Scholar 

  14. Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat rev Clin oncol. 2018;15:234–48.

  15. Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer. 2016;138:2570–8.

    Article  CAS  PubMed  Google Scholar 

  16. Becker S, Groner B, Muller C. Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature. 1998;394:P.145–151.

    Article  Google Scholar 

  17. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95–98.

    Article  CAS  PubMed  Google Scholar 

  18. Bai L, Zhou H, Xu R, Zhao Y, Chinnaswamy K, McEachern D, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36:498–511.e417.

  19. Liu L, McBride KM, Reich NC. STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3. Proc Natl Acad Sci USA. 2005;102:8150–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Darnell Jr JE. STATs and gene regulation. Science. 1997;277:1630–5.

  21. Levy DE, Darnell Jr JE. Signalling: Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–62.

  22. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–46.

    Article  CAS  PubMed  Google Scholar 

  23. Horiguchi A, Asano T, Kuroda K, Sato A, Asakuma J, Ito K, et al. STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br J cancer. 2010;102:1592–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res. 2007;67:9630–6.

    Article  CAS  PubMed  Google Scholar 

  25. Shin-Yi C, Chen YH, Lin PR, Chao TC, Su JC, Chung-Wai S, et al. Two novel SHP-1 agonists, SC-43 and SC-78, are more potent than regorafenib in suppressing the in vitro stemness of human colorectal cancer cells. Cell Death Discov. 2018;5:25.

  26. Tai WT, Shiau CW, Chen PJ, Chu PY, Huang HP, Liu CY. et al. Discovery of novel Src homology region 2 domain-containing phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology (Baltimore. Md). 2014;59:190–201.

    Article  CAS  Google Scholar 

  27. Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015;7:314ra185.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Jonker DJ, Nott L, Yoshino T, Gill S, Shapiro J, Ohtsu A, et al. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol Hepatol. 2018;3:263–70.

    Article  PubMed  Google Scholar 

  29. Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117:5701–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. David B, Wolfender JL, Dias DA. The pharmaceutical industry and natural products: historical status and new trends. Phytochemistry Rev. 2015;14:299–315.

    Article  CAS  Google Scholar 

  31. Buenz EJ, Verpoorte R, Bauer BA. The ethnopharmacologic contribution to bioprospecting natural products. Annu Rev Pharm Toxicol. 2018;58:509–30.

    Article  CAS  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Newman RA, Yang P, Pawlus AD, Block KI. Cardiac glycosides as novel cancer therapeutic agents. Mol interventions. 2008;8:36–49.

    Article  CAS  Google Scholar 

  34. Spera D, Siciliano T, De Tommasi N, Braca A, Vessières A. Antiproliferative cardenolides from Periploca graeca. Planta Med. 2007;73:384–7.

    Article  CAS  PubMed  Google Scholar 

  35. Han N, Yang J, Li L, Xiao B, Sha S, Tran L, et al. Inhibitory activity of a phytochemically characterized fraction from Streptocaulon juventas on lung cancer in nude mice. Planta Med. 2010;76:561–5.

    Article  CAS  PubMed  Google Scholar 

  36. Yang Y, Liu Y, Zhang Y, Ji W, Wang L, Lee SC. Periplogenin activates ROS-ER stress pathway to trigger apoptosis via BIP-eIF2alpha- CHOP and IRE1alpha-ASK1-JNK signaling routes. Anticancer Agents Med Chem. 2021;21:61–70.

    Article  PubMed  Google Scholar 

  37. Lohberger B, Wagner S, Wohlmuther J, Kaltenegger H, Stuendl N, Leithner A, et al. Periplocin, the most anti-proliferative constituent of Periploca sepium, specifically kills liposarcoma cells by death receptor mediated apoptosis. Phytomedicine. 2018;51:162–70.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang T, Li S, Li J, Yin F, Hua Y, Wang Z, et al. Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition. Cell Death Dis. 2016;7:e2421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ye H, Wei X, Meng C, Wei Y, Liang G, Huang Z, et al. Mechanism of action of periplogenin on nasopharyngeal carcinoma based on network pharmacology and experimental study of vitamin E coupled with periplogenin self-assembled nano-prodrug for nasopharyngeal carcinoma. J Biomed Nanotechnol. 2020;16:1406–15.

    Article  CAS  PubMed  Google Scholar 

  40. Shen ZY, Xu LY, Li EM, Shen J, Zheng RM, Cai WJ, et al. Immortal phenotype of the esophageal epithelial cells in the process of immortalization. Int J Mol Med. 2002;10:641–6.

    PubMed  Google Scholar 

  41. Carpenter RL, Lo HW. STAT3 target genes relevant to human cancers. Cancers (Basel). 2014;6:897–925.

    Article  CAS  Google Scholar 

  42. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994;76:821–8.

    Article  CAS  PubMed  Google Scholar 

  43. Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene. 2002;21:8404–13.

    Article  CAS  PubMed  Google Scholar 

  44. Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, et al. Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res. 2006;66:2544–52.

    Article  CAS  PubMed  Google Scholar 

  45. Hindley C, Philpott A. The cell cycle and pluripotency. Biochem J. 2013;451:135–43.

    Article  CAS  PubMed  Google Scholar 

  46. Xiong A, Yang Z, Shen Y, Zhou J, Shen Q. Transcription Factor STAT3 as a novel molecular target for cancer prevention. Cancers (Basel). 2014;6:926–57.

    Article  Google Scholar 

  47. Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13:3989–98.

    Article  CAS  Google Scholar 

  48. Liu H, Shin SH, Chen H, Liu T, Li Z, Hu Y, et al. CDK12 and PAK2 as novel therapeutic targets for human gastric cancer. Theranostics. 2020;10:6201–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yuan Q, Dong CD, Ge Y, Chen X, Li Z, Li X, et al. Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma. Aging (Albany NY). 2019;11:9530–43.

    Article  CAS  Google Scholar 

  50. Silva KA, Dong J, Dong Y, Dong Y, Schor N, Tweardy DJ, et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem. 2015;290:11177–87.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA. 2015;112:1839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol (Baltim, Md: 1950). 2013;191:3568–77.

    Article  Google Scholar 

  54. Phillips TJ, Forero-Torres A, Sher T, Diefenbach CS, Johnston P, Talpaz M, et al. Phase 1 study of the PI3Kδ inhibitor INCB040093±JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma. Blood. 2018;132:293–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gadina M, Johnson C, Schwartz D, Bonelli M, Hasni S, Kanno Y, et al. Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J Leukoc Biol. 2018;104:499–514.

    Article  CAS  PubMed  Google Scholar 

  56. Yang J, Stark GR. Roles of unphosphorylated STATs in signaling. Cell Res. 2008;18:443–51.

    Article  CAS  PubMed  Google Scholar 

  57. Zhang HY, Xu WQ, Wang YW, Omari-Siaw E, Wang Y, Zheng YY, et al. Tumor targeted delivery of octreotide-periplogenin conjugate: Synthesis, in vitro and in vivo evaluation. Int J Pharm. 2016;502:98–106.

  58. Li Z, Li Y, Li J, Liu R, Hao J, He J, et al. An LC-MS/MS method for simultaneous determination of the toxic and active components of cortex periplocae in rat plasma and application to a pharmacokinetic study. Int J Anal Chem. 2019;2019:1639619.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47:W357–W364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a grant from the National Science Foundation of China (No. 81872335); Henan Key Science and Technology Program 161100510300; National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (No. 2018ZX09711002). We thank Kyle Vaughn Laster, PhD, from China-US (Henan) Hormel Cancer Institute for polishing parts of this manuscript.

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Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450001, China

    Yamei Hu, Fangfang Liu, Xuechao Jia, Penglei Wang, Tingxuan Gu, Hui Liu, Tingting Liu, Huifang Wei, Yingying Chen, Zigang Dong & Kangdong Liu

  2. China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China

    Yamei Hu, Fangfang Liu, Xuechao Jia, Penglei Wang, Tingxuan Gu, Hui Liu, Tingting Liu, Huifang Wei, Ran Yang, Zigang Dong & Kangdong Liu

  3. Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, Henan, China

    Kangdong Liu

  4. Cancer chemoprevention international collaboration laboratory, Zhengzhou, Henan, China

    Kangdong Liu

  5. State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China

    Zigang Dong & Kangdong Liu

  6. The Hormel Institute, University of Minnesota, Austin, MN55912, USA

    Hanyong Chen

  7. Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, 450008, China

    Jiuzhou Zhao

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Contributions

YMH: Design, methodology, data curation, and writing; YMH: Editing; FFL, XCJ, PLW, TXG, HL, TTL, HFW, RY: Discussion; YMH, YYC: Validation; HYC, JZZ: Software; KDL, ZGD: Conception, Supervision.

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Correspondence to Zigang Dong or Kangdong Liu.

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Hu, Y., Liu, F., Jia, X. et al. Periplogenin suppresses the growth of esophageal squamous cell carcinoma in vitro and in vivo by targeting STAT3. Oncogene 40, 3942–3958 (2021). https://doi.org/10.1038/s41388-021-01817-2

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