The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Delphinidin enhances radio-therapeutic effects via autophagy induction and JNK/MAPK pathway activation in non-small cell lung cancer

  • Kang, Seong Hee (Research Division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI)) ;
  • Bak, Dong-Ho (Research Division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI)) ;
  • Chung, Byung Yeoup (Research Division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI)) ;
  • Bai, Hyoung-Woo (Research Division for Biotechnology, Advanced Radiation Technology Institute (ARTI), Korea Atomic Energy Research Institute (KAERI)) ;
  • Kang, Bo Sun (Department of Medical Science, Konyang University)
  • Received : 2020.03.10
  • Accepted : 2020.06.29
  • Published : 2020.09.01
Download PDF
⟨ Previous Next ⟩

Abstract

Delphinidin is a major anthocyanidin compound found in various vegetables and fruits. It has anti-oxidant, anti-inflammatory, and various other biological activities. In this study we demonstrated the anti-cancer activity of delphinidin, which was related to autophagy, in radiation-exposed non-small cell lung cancer (NSCLC). Radiosensitising effects were assessed in vitro by treating cells with a subcytotoxic dose of delphinidin (5 μM) before exposure to γ-ionising radiation (IR). We found that treatment with delphinidin or IR induced NSCLC cell death in vitro; however the combination of delphinidin pre-treatment and IR was more effective than either agent alone, yielding a radiation enhancement ratio of 1.54 at the 50% lethal dose. Moreover, combined treatment with delphinidin and IR, enhanced apoptotic cell death, suppressed the mTOR pathway, and activated the JNK/MAPK pathway. Delphinidin inhibited the phosphorylation of PI3K, AKT, and mTOR, and increased the expression of autophagy-induced cell death associated-protein in radiation-exposed NSCLC cells. In addition, JNK phosphorylation was upregulated by delphinidin pre-treatment in radiation-exposed NSCLC cells. Collectively, these results show that delphinidin acts as a radiation-sensitizing agent through autophagy induction and JNK/MAPK pathway activation, thus enhancing apoptotic cell death in NSCLC cells.

Keywords

References

  1. Tsuyuki S, Fukui S, Watanabe A, Akune S, Tanabe M, Yoshida K. Delphinidin induces autolysosome as well as autophagosome formation and delphinidin-induced autophagy exerts a cell protective role. J Biochem Mol Toxicol. 2012;26:445-453. https://doi.org/10.1002/jbt.21443
  2. Wang H, Nair MG, Strasburg GM, Chang YC, Booren AM, Gray JI, DeWitt DL. Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries. J Nat Prod. 1999;62:294-296. https://doi.org/10.1021/np980501m
  3. Kim B, Lee SG, Park YK, Ku CS, Pham TX, Wegner CJ, Yang Y, Koo SI, Chun OK, Lee JY. Blueberry, blackberry, and blackcurrant differentially affect plasma lipids and pro-inflammatory markers in dietinduced obesity mice. Nutr Res Pract. 2016;10:494-500. https://doi.org/10.4162/nrp.2016.10.5.494
  4. Kasten-Pisula U, Windhorst S, Dahm-Daphi J, Mayr G, Dikomey E. Radiosensitization of tumour cell lines by the polyphenol Gossypol results from depressed double-strand break repair and not from enhanced apoptosis. Radiother Oncol. 2007;83:296-303. https://doi.org/10.1016/j.radonc.2007.04.024
  5. Bump EA, Hoffman SJ, Foye WO. Radiosensitizers and radioprotective agents. In: Abraham DJ, editor. Burger's medicinal chemistry and drug discovery. 6th ed. Hoboken (NJ): Wiley; 2003. p.151-214.
  6. Nambiar D, Rajamani P, Singh RP. Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy. Mutat Res. 2011;728:139-157. https://doi.org/10.1016/j.mrrev.2011.07.005
  7. Kim MH, Jeong YJ, Cho HJ, Hoe HS, Park KK, Park YY, Choi YH, Kim CH, Chang HW, Park YJ, Chung IK, Chang YC. Delphinidin inhibits angiogenesis through the suppression of HIF-$1{\alpha}$ and VEGF expression in A549 lung cancer cells. Oncol Rep. 2017;37:777-784. https://doi.org/10.3892/or.2016.5296
  8. Jeong MH, Ko H, Jeon H, Sung GJ, Park SY, Jun WJ, Lee YH, Lee J, Lee SW, Yoon HG, Choi KC. Delphinidin induces apoptosis via cleaved HDAC3-mediated p53 acetylation and oligomerization in prostate cancer cells. Oncotarget. 2016;7:56767-56780. https://doi.org/10.18632/oncotarget.10790
  9. Chen J, Zhou J, Li F, Zhu Y, Zhang W, Yu X. [Delphinidin induces autophagy in HER-2+ breast cancer cells via inhibition of AKT/mTOR pathway]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017;42:264-270. Chinese.
  10. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27-42. https://doi.org/10.1016/j.cell.2007.12.018
  11. Jin S, White E. Role of autophagy in cancer: management of metabolic stress. Autophagy. 2007;3:28-31. https://doi.org/10.4161/auto.3269
  12. Kondo Y, Kondo S. Autophagy and cancer therapy. Autophagy. 2006;2:85-90. https://doi.org/10.4161/auto.2.2.2463
  13. Bialik S, Dasari SK, Kimchi A. Autophagy-dependent cell death - where, how and why a cell eats itself to death. J Cell Sci. 2018;131:jcs215152. https://doi.org/10.1242/jcs.215152
  14. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;23:2891-2906. https://doi.org/10.1038/sj.onc.1207521
  15. Kim TH, Kim HS, Kang YJ, Yoon S, Lee J, Choi WS, Jung JH, Kim HS. Psammaplin A induces Sirtuin 1-dependent autophagic cell death in doxorubicin-resistant MCF-7/adr human breast cancer cells and xenografts. Biochim Biophys Acta. 2015;1850:401-410. https://doi.org/10.1016/j.bbagen.2014.11.007
  16. Mohammadpour R, Safarian S, Ejeian F, Sheikholya-Lavasani Z, Abdolmohammadi MH, Sheinabi N. Acetazolamide triggers death inducing autophagy in T-47D breast cancer cells. Cell Biol Int. 2014;38:228-238. https://doi.org/10.1002/cbin.10197
  17. Kulkarni YM, Kaushik V, Azad N, Wright C, Rojanasakul Y, O'Doherty G, Iyer AK. Autophagy-induced apoptosis in lung cancer cells by a novel digitoxin analog. J Cell Physiol. 2016;231:817-828. https://doi.org/10.1002/jcp.25129
  18. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell. 2006;10:51-64. https://doi.org/10.1016/j.ccr.2006.06.001
  19. Liu L, Liao JZ, He XX, Li PY. The role of autophagy in hepatocellular carcinoma: friend or foe. Oncotarget. 2017;8:57707-57722. https://doi.org/10.18632/oncotarget.17202
  20. Feng R, Wang SY, Shi YH, Fan J, Yin XM. Delphinidin induces necrosis in hepatocellular carcinoma cells in the presence of 3-methyladenine, an autophagy inhibitor. J Agric Food Chem. 2010;58:3957-3964. https://doi.org/10.1021/jf9025458
  21. Lee DY, Park YJ, Hwang SC, Kim KD, Moon DK, Kim DH. Cytotoxic effects of delphinidin in human osteosarcoma cells. Acta Orthop Traumatol Turc. 2018;52:58-64. https://doi.org/10.1016/j.aott.2017.11.011
  22. Chen J, Zhu Y, Zhang W, Peng X, Zhou J, Li F, Han B, Liu X, Ou Y, Yu X. Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells. BMC Cancer. 2018;18:342. https://doi.org/10.1186/s12885-018-4231-y
  23. Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy. 2005;1:84-91. https://doi.org/10.4161/auto.1.2.1697
  24. Otomo C, Metlagel Z, Takaesu G, Otomo T. Structure of the human ATG12-ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol. 2013;20:59-66. https://doi.org/10.1038/nsmb.2431
  25. Mizushima N. Transgenic models of autophagy. In: Deretic V, editor. Autophagy in immunity and infection: a novel immune effector. Weinheim: Wiley-VCH; 2006. p.55-67.
  26. Hafeez BB, Siddiqui IA, Asim M, Malik A, Afaq F, Adhami VM, Saleem M, Din M, Mukhtar H. A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells in vitro and in vivo: involvement of nuclear factor-kappaB signaling. Cancer Res. 2008;68:8564-8572. https://doi.org/10.1158/0008-5472.CAN-08-2232
  27. Crighton D, Wilkinson S, Ryan KM. DRAM links autophagy to p53 and programmed cell death. Autophagy. 2007;3:72-74. https://doi.org/10.4161/auto.3438
  28. Crighton D, Wilkinson S, O'Prey J, Syed N, Smith P, Harrison PR, Gasco M, Garrone O, Crook T, Ryan KM. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126:121-134. https://doi.org/10.1016/j.cell.2006.05.034
  29. Wilkinson MG, Millar JB. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 2000;14:2147-2157. https://doi.org/10.1096/fj.00-0102rev
  30. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861-2873. https://doi.org/10.1101/gad.1599207
  31. Gewirtz DA. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74:647-651. https://doi.org/10.1158/0008-5472.CAN-13-2966
  32. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X, He C, Pan H. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838. https://doi.org/10.1038/cddis.2013.350
  33. Notte A, Leclere L, Michiels C. Autophagy as a mediator of chemotherapy-induced cell death in cancer. Biochem Pharmacol. 2011;82:427-434. https://doi.org/10.1016/j.bcp.2011.06.015
  34. Liu Q, Wang JJ, Pan YC, Meng LF, Zhan X, Zheng QF. [Expression of autophagy-related genes Beclin1 and MAPLC3 in non-small cell lung cancer]. Ai Zheng. 2008;27:25-29. Chinese.
  35. Jiang ZF, Shao LJ, Wang WM, Yan XB, Liu RY. Decreased expression of Beclin-1 and LC3 in human lung cancer. Mol Biol Rep. 2012;39:259-267. https://doi.org/10.1007/s11033-011-0734-1
  36. Fu LL, Cheng Y, Liu B. Beclin-1: autophagic regulator and therapeutic target in cancer. Int J Biochem Cell Biol. 2013;45:921-924. https://doi.org/10.1016/j.biocel.2013.02.007
  37. Valente G, Morani F, Nicotra G, Fusco N, Peracchio C, Titone R, Alabiso O, Arisio R, Katsaros D, Benedetto C, Isidoro C. Expression and clinical significance of the autophagy proteins BECLIN 1 and LC3 in ovarian cancer. Biomed Res Int. 2014;2014:462658. https://doi.org/10.1155/2014/462658
  38. Karagounis IV, Kalamida D, Mitrakas A, Pouliliou S, Liousia MV, Giatromanolaki A, Koukourakis MI. Repression of the autophagic response sensitises lung cancer cells to radiation and chemotherapy. Br J Cancer. 2016;115:312-321. https://doi.org/10.1038/bjc.2016.202
  39. Chu CT. Autophagic stress in neuronal injury and disease. J Neuropathol Exp Neurol. 2006;65:423-432. https://doi.org/10.1097/01.jnen.0000229233.75253.be
  40. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B, Bao JK. Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 2012;45:487-498. https://doi.org/10.1111/j.1365-2184.2012.00845.x
  41. Huang P, Han J, Hui L. MAPK signaling in inflammation-associated cancer development. Protein Cell. 2010;1:218-226. https://doi.org/10.1007/s13238-010-0019-9
  42. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9-18. https://doi.org/10.1038/sj.cr.7290105
  43. Kyriakis JM, Avruch J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol Rev. 2012;92:689-737. https://doi.org/10.1152/physrev.00028.2011
  44. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev. 2003;22:395-403. https://doi.org/10.1023/A:1023781114568
  45. Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120:3446-3456. https://doi.org/10.1002/cncr.28864
  46. Sui X, Kong N, Ye L, Han W, Zhou J, Zhang Q, He C, Pan H. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. 2014;344:174-179. https://doi.org/10.1016/j.canlet.2013.11.019
  47. Wong CH, Iskandar KB, Yadav SK, Hirpara JL, Loh T, Pervaiz S. Simultaneous induction of non-canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One. 2010;5:e9996. https://doi.org/10.1371/journal.pone.0009996
  48. Shajahan AN, Dobbin ZC, Hickman FE, Dakshanamurthy S, Clarke R. Tyrosine-phosphorylated caveolin-1 (Tyr-14) increases sensitivity to paclitaxel by inhibiting BCL2 and BCLxL proteins via c-Jun N-terminal kinase (JNK). J Biol Chem. 2012;287:17682-17692. https://doi.org/10.1074/jbc.M111.304022
  49. Tian PG, Jiang ZX, Li JH, Zhou Z, Zhang QH. Spliced XBP1 promotes macrophage survival and autophagy by interacting with Beclin-1. Biochem Biophys Res Commun. 2015;463:518-523. https://doi.org/10.1016/j.bbrc.2015.05.061

Cited by

  1. The Hallmarks of Flavonoids in Cancer vol.26, pp.7, 2020, https://doi.org/10.3390/molecules26072029
  2. UBR5 inhibits the radiosensitivity of non-small cell lung cancer cells via the activation of the PI3K/AKT pathway vol.69, pp.5, 2020, https://doi.org/10.1136/jim-2020-001736
  3. Delphinidin and Its Glycosides’ War on Cancer: Preclinical Perspectives vol.22, pp.21, 2021, https://doi.org/10.3390/ijms222111500