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RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer

Oncogene volume 38, pages 3903–3918 (2019)Cite this article

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Abstract

RUNX3 is frequently inactivated by DNA hypermethylation in numerous cancers. Here, we show that RUNX3 has an important role in modulating apoptosis in immediate response to tumor necrosis factor-related apoptosis-including ligand (TRAIL). Importantly, no combined effect of TRAIL and RUNX3 was observed in non-cancerous cells. We investigated the expression of the death receptors (DRs) DR4 and DR5, which are related to TRAIL resistance. Overexpression of RUNX3 increased DR5 expression via induction of the reactive oxygen species (ROS)-endoplasmic reticulum (ER) stress-effector CHOP. Reduction of DR5 markedly decreased apoptosis enhanced by the combined therapy of TRAIL and RUNX3. Interestingly, RUNX3 induced reactive oxygen species production by inhibiting SOD3 transcription via binding to the Superoxide dismutase 3 (SOD3) promoter. Additionally, the combined effect of TRAIL and RUNX3 decreased tumor growth in xenograft models. Our results demonstrate a direct role for RUNX3 in TRAIL-induced apoptosis via activation of DR5 and provide further support for RUNX3 as an anti-tumor.

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References

  1. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997;276:111–3.

    Article  CAS  Google Scholar 

  2. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 1997;16:5386–97.

    Article  CAS  Google Scholar 

  3. Yang F, Tay KH, Dong L, Thorne RF, Jiang CC, Yang E, et al. Cystatin B inhibition of TRAIL-induced apoptosis is associated with the protection of FLIP(L) from degradation by the E3 ligase itch in human melanoma cells. Cell Death Differ. 2010;17:1354–67.

    Article  CAS  Google Scholar 

  4. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008;8:782–98.

    Article  CAS  Google Scholar 

  5. Na YJ, Lee DH, Kim JL, Kim BR, Park SH, Jo MJ, et al. Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation. Int J Biochem Cell Biol. 2017;89:147–56.

    Article  CAS  Google Scholar 

  6. Lee DH, Rhee JG, Lee YJ. Reactive oxygen species up-regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin. Br J Pharmacol. 2009;157:1189–202.

    Article  CAS  Google Scholar 

  7. Lee DH, Kim DW, Jung CH, Lee YJ, Park D. Gingerol sensitizes TRAIL-induced apoptotic cell death of glioblastoma cells. Toxicol Appl Pharmacol. 2014;279:253–65.

    Article  CAS  Google Scholar 

  8. Shi K, Xue J, Fang Y, Bi H, Gao S, Yang D, et al. Inorganic Kernel-reconstituted lipoprotein biomimetic nanovehicles enable efficient targeting “Trojan Horse” delivery of STAT3-decoy oligonucleotide for overcoming TRAIL resistance. Theranostics. 2017;7:4480–97.

    Article  Google Scholar 

  9. Chawla-Sarkar M, Bae SI, Reu FJ, Jacobs BS, Lindner DJ, Borden EC. Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ. 2004;11:915–23.

    Article  CAS  Google Scholar 

  10. Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, et al. Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nat Med. 2007;13:1070–7.

    Article  CAS  Google Scholar 

  11. Kandasamy K, Srivastava RK. Role of the phosphatidylinositol 3’-kinase/PTEN/Akt kinase pathway in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in non-small cell lung cancer cells. Cancer Res. 2002;62:4929–37.

    CAS  PubMed  Google Scholar 

  12. Franco AV, Zhang XD, Van Berkel E, Sanders JE, Zhang XY, Thomas WD, et al. The role of NF-kappa B in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells. J Immunol. 2001;166:5337–45.

    Article  CAS  Google Scholar 

  13. Daga A, Karlovich CA, Dumstrei K, Banerjee U. Patterning of cells in the Drosophila eye by Lozenge, which shares homologous domains with AML1. Genes Dev. 1996;10:1194–205.

    Article  CAS  Google Scholar 

  14. Kania MA, Bonner AS, Duffy JB, Gergen JP. The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system. Genes Dev. 1990;4:1701–13.

    Article  CAS  Google Scholar 

  15. Ito Y. Molecular basis of tissue-specific gene expression mediated by the runt domain transcription factor PEBP2/CBF. Genes Cells. 1999;4:685–96.

    Article  CAS  Google Scholar 

  16. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002;109:113–24.

    Article  CAS  Google Scholar 

  17. Ito K, Liu Q, Salto-Tellez M, Yano T, Tada K, Ida H, et al. RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res. 2005;65:7743–50.

    Article  CAS  Google Scholar 

  18. Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T. Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neoplastic gastric epithelia. Cancer Sci. 2003;94:360–4.

    Article  CAS  Google Scholar 

  19. Kim BR, Kang MH, Kim JL, Na YJ, Park SH, Lee SI, et al. RUNX3 inhibits the metastasis and angiogenesis of colorectal cancer. Oncol Rep. 2016;36:2601–8.

    Article  CAS  Google Scholar 

  20. Chi XZ, Yang JO, Lee KY, Ito K, Sakakura C, Li QL, et al. RUNX3 suppresses gastric epithelial cell growth by inducingp21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD. Mol Cell Biol. 2005;25:8097–107.

    Article  CAS  Google Scholar 

  21. Zhang K. Integration of ER stress, oxidative stress and the inflammatory response in health and disease. Int J Clin Exp Med. 2010;3:33–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29.

    Article  CAS  Google Scholar 

  23. Glab JA, Doerflinger M, Nedeva C, Jose I, Mbogo GW, Paton JC, et al. DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell Death Differ. 2017;24:944–50.

    Article  CAS  Google Scholar 

  24. Jiang Y, Chen X, Fan M, Li H, Zhu W, Chen X, et al. TRAIL facilitates cytokine expression and macrophage migration during hypoxia/reoxygenation via ER stress-dependent NF-kappaB pathway. Mol Immunol. 2017;82:123–36.

    Article  CAS  Google Scholar 

  25. He K, Zheng X, Li M, Zhang L, Yu J. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation. Oncogene. 2016;35:148–57.

    Article  CAS  Google Scholar 

  26. Zlotorynski E. Apoptosis. DR5 unfolds ER stress. Nat Rev Mol Cell Biol. 2014;15:498–9.

    Article  Google Scholar 

  27. Lu M, Lawrence DA, Marsters S, Acosta-Alvear D, Kimmig P, Mendez AS, et al. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science. 2014;345:98–101.

    Article  CAS  Google Scholar 

  28. Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, et al. Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med. 2001;7:954–60.

    Article  CAS  Google Scholar 

  29. Prasad S, Kim JH, Gupta SC, Aggarwal BB. Targeting death receptors for TRAIL by agents designed by Mother Nature. Trends Pharmacol Sci. 2014;35:520–36.

    Article  CAS  Google Scholar 

  30. Boyce M, Yuan J. Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ. 2006;13:363–73.

    Article  CAS  Google Scholar 

  31. Lee DH, Sung KS, Guo ZS, Kwon WT, Bartlett DL, Oh SC, et al. TRAIL-induced caspase activation is a prerequisite for activation of the endoplasmic reticulum stress-induced signal transduction pathways. J Cell Biochem. 2016;117:1078–91.

    Article  CAS  Google Scholar 

  32. Toscano F, Fajoui ZE, Gay F, Lalaoui N, Parmentier B, Chayvialle JA, et al. P53-mediated upregulation of DcR1 impairs oxaliplatin/TRAIL-induced synergistic anti-tumour potential in colon cancer cells. Oncogene. 2008;27:4161–71.

    Article  CAS  Google Scholar 

  33. Kodach LL, Jacobs RJ, Heijmans J, van Noesel CJ, Langers AM, Verspaget HW, et al. The role of EZH2 and DNA methylation in the silencing of the tumour suppressor RUNX3 in colorectal cancer. Carcinogenesis. 2010;31:1567–75.

    Article  CAS  Google Scholar 

  34. Ku JL, Kang SB, Shin YK, Kang HC, Hong SH, Kim IJ, et al. Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene. 2004;23:6736–42.

    Article  CAS  Google Scholar 

  35. Gan H, Hao Q, Idell S, Tang H. Transcription factor Runx3 is induced by influenza A virus and double-strand RNA and mediates airway epithelial cell apoptosis. Sci Rep. 2015;5:17916.

    Article  CAS  Google Scholar 

  36. Gan H, Hao Q, Idell S, Tang H. Interferon-gamma promotes double-stranded RNA-induced TLR3-dependent apoptosis via upregulation of transcription factor Runx3 in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2016;311:L1101–L12.

    Article  Google Scholar 

  37. Lee JH, Pyon JK, Kim DW, Lee SH, Nam HS, Kang SG, et al. Expression of RUNX3 in skin cancers. Clin Exp Dermatol. 2011;36:769–74.

    Article  CAS  Google Scholar 

  38. Lotem J, Levanon D, Negreanu V, Bauer O, Hantisteanu S, Dicken J, et al. Runx3 at the interface of immunity, inflammation and cancer. Biochim Biophys Acta. 2015;1855:131–43.

    CAS  PubMed  Google Scholar 

  39. Park SH, Lee DH, Kim JL, Kim BR, Na YJ, Jo MJ, et al. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. Oncotarget. 2016;7:59503–18.

    PubMed  PubMed Central  Google Scholar 

  40. Harashima N, Takenaga K, Akimoto M, Harada M. HIF-2alpha dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression. Oncotarget. 2017;8:42887–900.

    Article  Google Scholar 

  41. Dufour F, Rattier T, Constantinescu AA, Zischler L, Morle A, Ben Mabrouk H, et al. TRAIL receptor gene editing unveils TRAIL-R1 as a master player of apoptosis induced by TRAIL and ER stress. Oncotarget. 2017;8:9974–85.

    Article  Google Scholar 

  42. Iurlaro R, Puschel F, Leon-Annicchiarico CL, O’Connor H, Martin SJ, Palou-Gramon D, et al. Glucose deprivation induces ATF4-mediated apoptosis through TRAIL death receptors. Mol Cell Biol. 2017;37:e00479–16.

  43. Li T, Su L, Lei Y, Liu X, Zhang Y, Liu X. DDIT3 and KAT2A proteins regulate TNFRSF10A and TNFRSF10B expression in endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells. J Biol Chem. 2015;290:11108–18.

    Article  CAS  Google Scholar 

  44. Tian X, Ye J, Alonso-Basanta M, Hahn SM, Koumenis C, Dorsey JF. Modulation of CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 expression by nelfinavir sensitizes glioblastoma multiforme cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Biol Chem. 2011;286:29408–16.

    Article  CAS  Google Scholar 

  45. Liu Z, Shi Q, Song X, Wang Y, Wang Y, Song E, et al. Activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) cascade shows an essential role in the ER stress-induced sensitization of tetrachlorobenzoquinone-challenged PC12 cells to ROS-mediated apoptosis via death receptor 5 (DR5) signaling. Chem Res Toxicol. 2016;29:1510–8.

    Article  CAS  Google Scholar 

  46. Kapur A, Felder M, Fass L, Kaur J, Czarnecki A, Rathi K, et al. Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation. Sci Rep. 2016;6:27530.

    Article  CAS  Google Scholar 

  47. Ma Z, Fan C, Yang Y, Di S, Hu W, Li T, et al. Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation. Sci Rep. 2016;6:35196.

    Article  CAS  Google Scholar 

  48. Guha P, Kaptan E, Gade P, Kalvakolanu DV, Ahmed H. Tunicamycin induced endoplasmic reticulum stress promotes apoptosis of prostate cancer cells by activating mTORC1. Oncotarget. 2017;8:68191–207.

    Article  Google Scholar 

  49. Park HS, Jun do Y, Han CR, Woo HJ, Kim YH. Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells. Biochem Pharmacol. 2011;82:1110–25.

    Article  CAS  Google Scholar 

  50. He L, Jang JH, Choi HG, Lee SM, Nan MH, Jeong SJ, et al. Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression. Mol Carcinog. 2013;52:85–93.

    Article  Google Scholar 

  51. Lim JH, Park JW, Choi KS, Park YB, Kwon TK. Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC delta-independent mechanism in human malignant tumor cells. Carcinogenesis. 2009;30:729–36.

    Article  CAS  Google Scholar 

  52. Giambra V, Jenkins CR, Wang H, Lam SH, Shevchuk OO, Nemirovsky O, et al. NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-theta and reactive oxygen species. Nat Med. 2012;18:1693–8.

    Article  CAS  Google Scholar 

  53. Hartwig T, Montinaro A, von Karstedt S, Sevko A, Surinova S, Chakravarthy A, et al. The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Mol Cell. 2017;65:730–42 e5.

    Article  CAS  Google Scholar 

  54. Pal S, Amin PJ, Sainis KB, Shankar BS. Potential role of TRAIL in metastasis of mutant KRAS expressing lung adenocarcinoma. Cancer Microenviron. 2016;9:77–84.

    Article  CAS  Google Scholar 

  55. Fritsche H, Heilmann T, Tower RJ, Hauser C, von Au A, El-Sheikh D, et al. TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model. Oncotarget. 2015;6:9502–16.

    PubMed  PubMed Central  Google Scholar 

  56. von Karstedt S, Conti A, Nobis M, Montinaro A, Hartwig T, Lemke J, et al. Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. Cancer Cell. 2015;27:561–73.

    Article  Google Scholar 

  57. Kadara H, Lacroix L, Lotan D, Lotan R. Induction of endoplasmic reticulum stress by the pro-apoptotic retinoid N-(4-hydroxyphenyl)retinamide via a reactive oxygen species-dependent mechanism in human head and neck cancer cells. Cancer Biol Ther. 2007;6:705–11.

    Article  CAS  Google Scholar 

  58. Jung EM, Lim JH, Lee TJ, Park JW, Choi KS, Kwon TK. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis. 2005;26:1905–13.

    Article  CAS  Google Scholar 

  59. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4:181–9.

    Article  CAS  Google Scholar 

  60. Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal. 2011;15:1583–606.

    Article  CAS  Google Scholar 

  61. Kim BR, Jeong YA, Na YJ, Park SH, Jo MJ, Kim JL, et al. Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway. Oncotarget. 2017;8:101952–64.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a National Research Foundation (NRF) of Korea grant funded the Korean government (MSIP) [NRF-2017R1A6A3A11030765] and was supported by Korea University Grant and was supported by project for cooperative R&D between Industry, Academy, and Research Institute funded Korea ministry of SMES and Startups in 2018 [Grants No. Co558375].

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  1. Department of Oncology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea

    Bo Ram Kim, Jung Lim Kim, Soyeon Jeong, Sang Cheul Oh & Dae-Hee Lee

  2. Graduate School of Medicine, Korea University College of Medicine, Seoul, Republic of Korea

    Seong Hye Park, Yoon A Jeong, Yoo Jin Na, Min Jee Jo & Hye Kyeong Yun

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Kim, B.R., Park, S.H., Jeong, Y.A. et al. RUNX3 enhances TRAIL-induced apoptosis by upregulating DR5 in colorectal cancer. Oncogene 38, 3903–3918 (2019). https://doi.org/10.1038/s41388-019-0693-x

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