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Triptolide: Regulator of Cellular Metabolism of Significant Fraction of Small Cell Lung Cancer via lncRNAs

Year 2021, Volume: 4 Issue: 3, 95 - 103, 29.09.2021

Abstract

Objective: Small cell lung cancer accounts for 15% of all lung cancer cases. Myc family is frequently amplified and/or overexpressed in 20% of small cell lung cancers and can promote carcinogenesis. Triptolide, a Chinese medicinal herb, is an anticancer reagent isolated from Tripterygium wilfordii Hook f. This study aimed to investigate Triptolide's possible effect on Myc overexpressed/ amplified SCLC cells. Materials and methods: To determine the expression of Myc and Myc-dependent metabolic genes, H209, H209myc, N417, and Lu135 cells were treated with Triptolide, and expression levels of Myc and associated lncRNAs were measured by qRT-PCR. Western blot analysis was performed to evaluate Myc, p21, cyclin D1 expressions. Besides, glucose uptake activity was assessed in the triptolide-treated cells. Results: We have observed that Triptolide inhibited the proliferation of SCLC cells by inhibiting MYC expression. Triptolide has been found to repress cellular proliferation, glucose metabolism, and glucose uptake, resulting in decreased Glut1, Glut4, HK2, LDHA, and Eno1. Triptolide changed the expressions of cellular proliferation and metabolism-related lncRNAs (ANRIL, PVT1, PTENP1, H19, and lincRNA-p21). Conclusion: The results have strongly indicated that triptolide treatment reduces cellular proliferation and glucose metabolism by regulating lncRNA expressions. Triptolide treatment would be a promising therapeutic strategy for SCLC.

References

  • 1. Santarpia M, Daffinà MG, Karachaliou N, González-Cao M, Lazzari C, Altavilla G, et al. Targeted drugs in small-cell lung cancer. Transl Lung Cancer Res 2016;5(1):51-70.
  • 2. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know, and the path forward. Nat Rev Cancer 2017;10:17(12):765.
  • 3. Deneka AY, Boumber Y, Beck T, Golemis EA. Tumor-Targeted Drug Conjugates as an Emerging Novel Therapeutic Approach in Small Cell Lung Cancer (SCLC). Cancers (Basel) 2019;11(9):1297.
  • 4. Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res 2016;5(1):16-25. 5. Taniguchi H, Sen T, Rudin CM. Targeted Therapies and Biomarkers in Small Cell Lung Cancer. Front Oncol 2020;10:741.
  • 6. Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, Stastny V, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 2018;7(1):32-49.
  • 7. Lüscher B, Vervoorts J. Regulation of gene transcription by the oncoprotein MYC. Gene 2012;494(2):145-60.
  • 8. Kress TR, Sabò A, Amati B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer 2015;(10):593-607.
  • 9. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM et al. MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell 2017;31(2):270-85.
  • 10. García-Gutiérrez L, Bretones G, Molina E, Arechaga I, Symonds C, Acosta JC et al. Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27. Sci Rep 2019;9(1):18693.
  • 11. Schwinkendorf D, Gallant P. The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo. Gene 2009;436(1-2): 90-100.
  • 12. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res 2012;18(20):5546-53.
  • 13. Tokgun O, Tokgun PE, Inci K, Akca H. lncRNAs as Potential Targets in Small Cell Lung Cancer: MYC -dependent Regulation. Anticancer Agents Med Chem. 2020;20(17):2074-81.
  • 14. Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 2004;24(13):5923-36.
  • 15. Huarte M. The emerging role of lncRNAs in cancer. Nat Med 2015;21:1253–61.
  • 16. Tokgun PE, Tokgun O, Kurt S. MYC-driven regulation of long non-coding RNA profiles in breast cancer cells. Gene 2019;25 (714):143955.
  • 17. Dong Y, Tu R, Liu H. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Sig Transduct Target Ther 2020;5(1):124.
  • 18. Dang CV. Therapeutic targeting of Mycreprogrammed cancer cell metabolism. Cold Spring Harb Symp Quant Biol 2011;76:369-74.
  • 19. Kato F, Fiorentino FP, Alibés A, Perucho M, Sánchez-Céspedes M, Kohno T et al. MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells. Oncotarget. 2016;7(47):77378-88.
  • 20. Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, Kohno T et al. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget 2016;7(21):31014-28.
  • 21. Noel P, Von Hoff DD, Saluja AK, Velagapudi M, Borazanci E, Han H. Triptolide and Its Derivatives as Cancer Therapies. Trends Pharmacol Sci 2019;40(5):327-41.
  • 22. Zhu J, Wang H, Chen F, Lv H, Xu Z, Fu J et al. Triptolide enhances chemotherapeutic efficacy of antitumor drugs in non-small-cell lung cancer cells by inhibiting Nrf2-ARE activity. Toxicol Appl Pharmacol 2018;358:1-9.
  • 23. Chen SR, Dai Y, Zhao J, Lin L, Wang Y, Wang Y. A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F. Front Pharmacol 2018;9:104.
  • 24. Kong J, Wang L, Ren L, Yan Y, Cheng Y, Huang Z et al. Triptolide induces mitochondriamediated apoptosis of Burkitt’s lymphoma cell via deacetylation of GSK-3β by increased SIRT3 expression. Toxicol Appl Pharmacol 2018;342:1- 13.
  • 25. Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 1985;45(6):2913-23.
  • 26. Lu W, Cao F, Wang S, Sheng X, Ma J. LncRNAs: The Regulator of Glucose and Lipid Metabolism in Tumor Cells. Front Oncol 2019;9:1099.

Triptolit: Küçük Hücreli Akciğer Kanserinin Önemli Fraksiyonunun lncRNA'lar aracılı Hücresel Metabolizmasının Düzenleyicisi

Year 2021, Volume: 4 Issue: 3, 95 - 103, 29.09.2021

Abstract

Amaç: Küçük hücreli akciğer kanseri (KHAK), tüm akciğer kanseri vakalarının %15'ini oluşturmaktadır. Myc ailesi, küçük hücreli akciğer kanserlerinin %20'sinde sıklıkla amplifiye/ aşırı eksprese edilir ve karsinogenezi indüklemektedir. Bir Çin şifalı bitkisi olan Triptolit, Tripterygium wilfordii Hook f 'den izole edilen bir antikanser moleküldür. Bu çalışma, Triptolit'in Myc aşırı eksprese/amplifiye KHAK hücreleri üzerindeki olası etkisini araştırmayı amaçlamıştır. Materyal ve metod: Myc ve Myc'ye bağlı metabolik genlerin ekspresyonunu belirlemek için H209, H209myc, N417 ve Lu135 hücreleri Triptolit ile muamele edildi ve Myc ve ilişkili lncRNA'ların ekspresyon seviyeleri qRT-PCR ile analiz edildi. Myc, p21, siklin D1 protein ifadelerini değerlendirmek için Western blot analizi yapıldı. Ayrıca, triptolit ile muamele edilmiş hücrelerde glikoz alınım aktivitesi ölçüldü. Bulgular: Triptolit'in MYC ekspresyonunu inhibe ederek KHAK hücrelerinin proliferasyonunu baskıladığını gözlemledik. Triptolitin hücresel proliferasyonu, glikoz metabolizmasını ve glikoz alımını inhibe ettiği ve Glut1, Glut4, HK2, LDHA ve Eno1 ifadelerinde azalmaya neden olduğu saptandı. Triptolit’in hücresel proliferasyon ve metabolizma ile ilişkili lncRNA'ların (ANRIL, PVT1, PTENP1, H19 ve lincRNA-p21) ifadelerini düzenlediği gözlemlendi. Sonuç: Sonuçlar, triptolit tedavisinin lncRNA ekspresyonlarını düzenleyerek hücresel proliferasyonu ve glikoz metabolizmasını baskıladığını güçlü bir şekilde göstermiştir. Triptolit tedavisinin KHAK için umut verici bir terapötik strateji olacağını düşünmekteyiz.

References

  • 1. Santarpia M, Daffinà MG, Karachaliou N, González-Cao M, Lazzari C, Altavilla G, et al. Targeted drugs in small-cell lung cancer. Transl Lung Cancer Res 2016;5(1):51-70.
  • 2. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know, and the path forward. Nat Rev Cancer 2017;10:17(12):765.
  • 3. Deneka AY, Boumber Y, Beck T, Golemis EA. Tumor-Targeted Drug Conjugates as an Emerging Novel Therapeutic Approach in Small Cell Lung Cancer (SCLC). Cancers (Basel) 2019;11(9):1297.
  • 4. Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res 2016;5(1):16-25. 5. Taniguchi H, Sen T, Rudin CM. Targeted Therapies and Biomarkers in Small Cell Lung Cancer. Front Oncol 2020;10:741.
  • 6. Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, Stastny V, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 2018;7(1):32-49.
  • 7. Lüscher B, Vervoorts J. Regulation of gene transcription by the oncoprotein MYC. Gene 2012;494(2):145-60.
  • 8. Kress TR, Sabò A, Amati B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer 2015;(10):593-607.
  • 9. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM et al. MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition. Cancer Cell 2017;31(2):270-85.
  • 10. García-Gutiérrez L, Bretones G, Molina E, Arechaga I, Symonds C, Acosta JC et al. Myc stimulates cell cycle progression through the activation of Cdk1 and phosphorylation of p27. Sci Rep 2019;9(1):18693.
  • 11. Schwinkendorf D, Gallant P. The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo. Gene 2009;436(1-2): 90-100.
  • 12. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res 2012;18(20):5546-53.
  • 13. Tokgun O, Tokgun PE, Inci K, Akca H. lncRNAs as Potential Targets in Small Cell Lung Cancer: MYC -dependent Regulation. Anticancer Agents Med Chem. 2020;20(17):2074-81.
  • 14. Kim JW, Zeller KI, Wang Y, Jegga AG, Aronow BJ, O’Donnell KA, et al. Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol Cell Biol 2004;24(13):5923-36.
  • 15. Huarte M. The emerging role of lncRNAs in cancer. Nat Med 2015;21:1253–61.
  • 16. Tokgun PE, Tokgun O, Kurt S. MYC-driven regulation of long non-coding RNA profiles in breast cancer cells. Gene 2019;25 (714):143955.
  • 17. Dong Y, Tu R, Liu H. Regulation of cancer cell metabolism: oncogenic MYC in the driver’s seat. Sig Transduct Target Ther 2020;5(1):124.
  • 18. Dang CV. Therapeutic targeting of Mycreprogrammed cancer cell metabolism. Cold Spring Harb Symp Quant Biol 2011;76:369-74.
  • 19. Kato F, Fiorentino FP, Alibés A, Perucho M, Sánchez-Céspedes M, Kohno T et al. MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells. Oncotarget. 2016;7(47):77378-88.
  • 20. Fiorentino FP, Tokgün E, Solé-Sánchez S, Giampaolo S, Tokgün O, Jauset T, Kohno T et al. Growth suppression by MYC inhibition in small cell lung cancer cells with TP53 and RB1 inactivation. Oncotarget 2016;7(21):31014-28.
  • 21. Noel P, Von Hoff DD, Saluja AK, Velagapudi M, Borazanci E, Han H. Triptolide and Its Derivatives as Cancer Therapies. Trends Pharmacol Sci 2019;40(5):327-41.
  • 22. Zhu J, Wang H, Chen F, Lv H, Xu Z, Fu J et al. Triptolide enhances chemotherapeutic efficacy of antitumor drugs in non-small-cell lung cancer cells by inhibiting Nrf2-ARE activity. Toxicol Appl Pharmacol 2018;358:1-9.
  • 23. Chen SR, Dai Y, Zhao J, Lin L, Wang Y, Wang Y. A Mechanistic Overview of Triptolide and Celastrol, Natural Products from Tripterygium wilfordii Hook F. Front Pharmacol 2018;9:104.
  • 24. Kong J, Wang L, Ren L, Yan Y, Cheng Y, Huang Z et al. Triptolide induces mitochondriamediated apoptosis of Burkitt’s lymphoma cell via deacetylation of GSK-3β by increased SIRT3 expression. Toxicol Appl Pharmacol 2018;342:1- 13.
  • 25. Carney DN, Gazdar AF, Bepler G, Guccion JG, Marangos PJ, Moody TW et al. Establishment and identification of small cell lung cancer cell lines having classic and variant features. Cancer Res 1985;45(6):2913-23.
  • 26. Lu W, Cao F, Wang S, Sheng X, Ma J. LncRNAs: The Regulator of Glucose and Lipid Metabolism in Tumor Cells. Front Oncol 2019;9:1099.
There are 25 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Article
Authors

Onur Tokgün 0000-0003-0537-9032

Kubilay Incı 0000-0001-9341-7945

Publication Date September 29, 2021
Submission Date May 19, 2021
Published in Issue Year 2021 Volume: 4 Issue: 3

Cite

MLA Tokgün, Onur and Kubilay Incı. “Triptolide: Regulator of Cellular Metabolism of Significant Fraction of Small Cell Lung Cancer via LncRNAs”. Sağlık Bilimlerinde İleri Araştırmalar Dergisi, vol. 4, no. 3, 2021, pp. 95-103.