DOI QR코드

DOI QR Code

Effect of punicalagin on the autophagic cell death in triple-negative breast cancer cells

  • Zeeshan Ahmad Bhutta (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Ryeo‑Eun Go (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University) ;
  • Kyung‑Chul Choi (Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University)
  • 투고 : 2024.01.25
  • 심사 : 2024.05.01
  • 발행 : 2024.10.15

초록

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), resulting in poor clinical outcomes and high mortality. The present study was aimed to evaluate the efficacy of Punicalagin (PCG), a polyphenol obtained from the Punica granatum, against TNBC. We evaluated the therapeutic potential of PCG in TNBC (MDA-MB-231, BT-20) and ER+(MCF-7) breast cancer cells. A dose-dependent inhibition of MDA-MB-231 cell proliferation was observed with PCG (12.5-100 µM). However, only 50 and 100 µM doses of PCG inhibited the growth of BT-20 and MCF-7 cells. PCG significantly increased mitochondrial ROS in TNBC cells and induced autophagy across all cell lines, as evidenced by an increase in autophagic vacuoles and a decrease in the ratio of LC3-II/LC3-I. PCG suppressed PI3K/Akt and activated phosphorylated c-Jun N-terminal kinase (p-JNK) signaling. Based on these findings, it can be concluded that PCG is capable of significantly inhibiting the proliferation of TNBC cells through the suppression of the PI3K/Akt pathway as well as the initiation of the JNK pathway. PCG could thus be potentially useful as a therapeutic agent for the treatment of TNBC.

키워드

과제정보

This work was supported by the Basic Research Lab Program (2022R1A4A1025557) through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science and ICT. In addition, this study was also supported by the "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE; 2021RIS-001) in 2024.

참고문헌

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBO-CAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209-249. https://doi.org/10.3322/caac.21660
  2. Maqbool M, Bekele F, Fekadu G (2023) Treatment strategies against triple-negative breast cancer: an updated review. Breast Cancer Targets Ther 14:15-24. https://doi.org/10.2147/BCTT.S348060
  3. Chang-Qing Y, Jie L, Shi-Qi Z, Kun Z, Zi-Qian G, Ran X, Hui-Meng L, Ren-Bin Z, Gang Z, Da-Chuan Y, Chen-Yan Z (2020) Recent treatment progress of triple negative breast cancer. Progress Biophys Mol Biol 151:40-53. https://doi.org/10.1016/j.pbiomolbio.2019.11.007
  4. Newman DJ, Cragg GM (2020) Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 83:770-803. https://doi.org/10.1021/acs.jnatprod.9b01285
  5. Shaygannia E, Bahmani M, Zamanzad B, Rafieian-Kopaei M (2016) A review study on Punica granatum L. J Evid Based Complement Altern Med 21:221-227. https://doi.org/10.1177/2156587215598039
  6. Berkoz M, Allahverdiyev O (2017) Punicalagin isolated from Punica granatum husk can decrease the inflammatory response in RAW 264.7 macrophages. East J Med 22:57-64. https://doi.org/10.5505/ejm.2017.08760
  7. Zhang Y, Tan X, Cao Y, An X, Chen J, Yang L (2022) Punicalagin protects against diabetic liver injury by upregulating mitophagy and antioxidant enzyme activities. Nutrients 14:2782. https://doi.org/10.3390/nu14142782
  8. Cao Y, Chen J, Ren G, Zhang Y, Tan X, Yang L (2019) Punicalagin prevents inflammation in LPS-induced RAW264.7 macrophages by inhibiting FoxO3a/autophagy signaling pathway. Nutrients 11:2794. https://doi.org/10.3390/nu11112794
  9. Berkoz M, Krosniak M (2020) Punicalagin induces apoptosis in A549 cell line through mitochondria-mediated pathway. Gen Physiol Biophys 39:557-567. https://doi.org/10.4149/gpb_2020024
  10. Liu C-H, Kuo Y-T, Lin C-J, Lin L-T (2023) Involvement of cell surface glycosaminoglycans in chebulagic acid's and punicalagin's antiviral activities against Coxsackievirus A16 infection. Phytomedicine 120:155047. https://doi.org/10.1016/j.phymed.2023.155047
  11. Cheng X, Gao Y, Yao X, Yu H, Bao J, Guan H, Sun Y, Zhang L (2016) Punicalagin induces apoptosis-independent autophagic cell death in human papillary thyroid carcinoma BCPAP cells. RSC Adv 6:68485-68493. https://doi.org/10.1039/C6RA13431A
  12. Ganesan T, Sinniah A, Chik Z, Alshawsh MA (2020) Punicalagin regulates apoptosis-autophagy switch via modulation of annexin A1 in colorectal cancer. Nutrients 12:2430. https://doi.org/10.3390/nu12082430
  13. Zhang L, Chinnathambi A, Alharbi SA, Veeraraghavan VP, Mohan SK, Zhang G (2020) Punicalagin promotes the apoptosis in human cervical cancer (ME-180) cells through mitochondrial pathway and by inhibiting the NF-kB signaling pathway. Saudi J Biol Sci 27:1100-1106. https://doi.org/10.1016/j.sjbs.2020.02.015
  14. Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158-167. https://doi.org/10.1016/j.molcel.2012.09.025
  15. Yang H, Villani RM, Wang H, Simpson MJ, Roberts MS, Tang M, Liang X (2018) The role of cellular reactive oxygen species in cancer chemotherapy. J Exp Clin Cancer Res 37:266. https://doi.org/10.1186/s13046-018-0909-x
  16. Okon IS, Zou MH (2015) Mitochondrial ROS and cancer drug resistance: implications for therapy. Pharmacol Res 100:170-174. https://doi.org/10.1016/j.phrs.2015.06.013
  17. Shah MA, Rogof HA (2021) Implications of reactive oxygen species on cancer formation and its treatment. Semin Oncol 48:238-245. https://doi.org/10.1053/j.seminoncol.2021.05.002
  18. Cao W, Li J, Yang K, Cao D (2021) An overview of autophagy: mechanism, regulation and research progress. Bull du Cancer 108:304-322. https://doi.org/10.1016/j.bulcan.2020.11.004
  19. Mulcahy Levy JM, Thorburn A (2020) Autophagy in cancer: moving from understanding mechanism to improving therapy responses in patients. Cell Death Differ 27:843-857. https://doi.org/10.1038/s41418-019-0474-7
  20. Booth L, Roberts JL, Poklepovic A, Dent P (2024) Autophagy as a therapeutic mechanism to kill drug-resistant cancer cells. Anticancer Drugs 35:177-182. https://doi.org/10.1097/cad.0000000000001549
  21. Sharma E, Attri DC, Sati P, Dhyani P, Szopa A, Sharif-Rad J, Hano C, Calina D, Cho WC (2022) Recent updates on anticancer mechanisms of polyphenols. Front Cell Develop Biol 10:1005910. https://doi.org/10.3389/fcell.2022.1005910
  22. Gupta N, Singh S, Chauhan D, Srivastava R, Singh VK (2023) Exploring the anticancer potentials of polyphenols: a comprehensive review of patents in the last five years. Recent Pat Anti-Cancer Drug Discov 18:3-10. https://doi.org/10.2174/1574892817666220512220036
  23. Kilit AC, Aydemir E (2023) Anticancer effects of punicalagin. Haydarpasa Numune Med J 63:99-104. https://doi.org/10.14744/hnhj.2021.77044
  24. Gao L, Wang Z, Lu D, Huang J, Liu J, Hong L (2019) Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells. Cell Death Dis 10:609. https://doi.org/10.1038/s41419-019-1849-x
  25. Kumar K, Sabarwal A, Singh RP (2019) Mancozeb selectively induces mitochondrial-mediated apoptosis in human gastric carcinoma cells through ROS generation. Mitochondrion 48:1-10. https://doi.org/10.1016/j.mito.2018.06.003
  26. Chen Y-F, Liu H, Luo X-J, Zhao Z, Zou Z-Y, Li J, Lin X-J, Liang Y (2017) The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells. Crit Rev Oncol/Hematol 112:21-30. https://doi.org/10.1016/j.critrevonc.2017.02.004
  27. Liu X-J, Wang Y-Q, Shang S-Q, Xu S, Guo M (2022) TMT induces apoptosis and necroptosis in mouse kidneys through oxidative stress-induced activation of the NLRP3 inflammasome. Ecotoxicol Environ Saf 230:113167. https://doi.org/10.1016/j.ecoenv.2022.113167
  28. Nakamura H, Takada K (2021) Reactive oxygen species in cancer: current findings and future directions. Cancer Sci 112:3945-3952. https://doi.org/10.1111/cas.15068
  29. Wei B, Huang Q, Huang S, Mai W, Zhong X (2016) Trichosanthin-induced autophagy in gastric cancer cell MKN-45 is dependent on reactive oxygen species (ROS) and NF-κB/p53 pathway. J Pharmacol Sci 131:77-83. https://doi.org/10.1016/j.jphs.2016.03.001
  30. Yi L-T, Dong S-Q, Wang S-S, Chen M, Li C-F, Geng D, Zhu J-X, Liu Q, Cheng J (2020) Curcumin attenuates cognitive impairment by enhancing autophagy in chemotherapy. Neurobiol Dis 136:104715. https://doi.org/10.1016/j.nbd.2019.104715
  31. Fang L, Wang H, Zhang J, Fang X (2021) Punicalagin induces ROS-mediated apoptotic cell death through inhibiting STAT3 translocation in lung cancer A549 cells. J Biochem Mol Toxicol 35:1-10. https://doi.org/10.1002/jbt.22771
  32. Xie X, Hu L, Liu L, Wang J, Liu Y, Ma L, Sun G, Li C, Aisa HA, Meng S (2022) Punicalagin promotes autophagic degradation of human papillomavirus E6 and E7 proteins in cervical cancer through the ROS-JNK-BCL2 pathway. Transl Oncol 19:101388. https://doi.org/10.1016/j.tranon.2022.101388
  33. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112-119. https://doi.org/10.1038/nchembio711
  34. Yan J, Wan P, Choksi S, Liu Z-G (2022) Necroptosis and tumor progression. Trends in Cancer 8:21-27. https://doi.org/10.1016/j.trecan.2021.09.003
  35. Zang X, Song J, Li Y, Han Y (2022) Targeting necroptosis as an alternative strategy in tumor treatment: from drugs to nanoparticles. J Control Release 349:213-226. https://doi.org/10.1016/j.jconrel.2022.06.060
  36. Yun CW, Jeon J, Go G, Lee JH, Lee SH (2020) The dual role of autophagy in cancer development and a therapeutic strategy for cancer by targeting autophagy. Int J Mol Sci 22:179. https://doi.org/10.3390/ijms22010179
  37. Fitzwalter BE, Thorburn A (2015) Recent insights into cell death and autophagy. FEBS J 282:4279-4288. https://doi.org/10.1111/febs.13515
  38. Subkorn P, Norkaew C, Deesrisak K, Tanyong D (2021) Punicalagin, a pomegranate compound, induces apoptosis and autophagy in acute leukemia. PeerJ 9:e12303. https://doi.org/10.7717/peerj.12303
  39. Hollenstein DM, Kraft C (2020) Autophagosomes are formed at a distinct cellular structure. Curr Opin Cell Biol 65:50-57. https://doi.org/10.1016/j.ceb.2020.02.012
  40. Mizushima N, Yoshimori T, Levine B (2010) Methods in mammalian autophagy research. Cell 140:313-326. https://doi.org/10.1016/j.cell.2010.01.028
  41. Park NY, Jo DS, Cho D-H (2022) Post-translational modifications of ATG4B in the regulation of autophagy. Cells 11:1330. https://doi.org/10.3390/cells11081330
  42. Seront E, Boidot R, Bouzin C, Karroum O, Jordan BF, Gallez B, Machiels JP, Feron O (2013) Tumour hypoxia determines the potential of combining mTOR and autophagy inhibitors to treat mammary tumours. Br J Cancer 109:2597-2606. https://doi.org/10.1038/bjc.2013.644
  43. Fujita N, Hayashi-Nishino M, Fukumoto H, Omori H, Yamamoto A, Noda T, Yoshimori T (2008) An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol Biol Cell 19:4651-4659. https://doi.org/10.1091/mbc.e08-03-0312
  44. Zhou Y, Wang Z, Huang Y, Bai C, Zhang X, Fang M, Ju Z, Liu B (2021) Membrane dynamics of ATG4B and LC3 in autophagosome formation. J Mol Cell Biol 13:853-863. https://doi.org/10.1093/jmcb/mjab059
  45. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749-1760. https://doi.org/10.1038/sj.emboj.7601623
  46. Bubici C, Papa S (2014) JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol 171:24-37. https://doi.org/10.1111/bph.12432
  47. Reczek CR, Chandel NS (2017) The two faces of reactive oxygen species in cancer. Ann Rev Cancer Biol 1:79-98. https://doi.org/10.1146/annurev-cancerbio-041916-065808
  48. Zheng Q, Li Q, Zhao G, Zhang J, Yuan H, Gong D, Guo Y, Liu X, Li K, Lin P (2020) Alkannin induces cytotoxic autophagy and apoptosis by promoting ROS-mediated mitochondrial dysfunction and activation of JNK pathway. Biochem Pharmacol 180:114167. https://doi.org/10.1016/j.bcp.2020.114167
  49. Liu G-y, Jiang X-x, Zhu X, He W-y, Kuang Y-l, Ren K, Lin Y, Gou X (2015) ROS activates JNK-mediated autophagy to counteract apoptosis in mouse mesenchymal stem cells in vitro. Acta Pharmacol Sin 36:1473-1479. https://doi.org/10.1038/aps.2015.101
  50. Han S-H, Lee J-H, Woo J-S, Jung G-H, Jung S-H, Han E-J, Park Y-S, Kim B-S, Kim S-K, Park B-K, Choi C, Jung J-Y (2022) Myricetin induces apoptosis through the MAPK pathway and regulates JNK-mediated autophagy in SK-BR-3 cells. Int J Mol Med 49:54. https://doi.org/10.3892/ijmm.2022.5110
  51. Kalai Selvi S, Vinoth A, Varadharajan T, Weng CF, Vijaya Padma V (2017) Neferine augments therapeutic efficacy of cisplatin through ROS-mediated non-canonical autophagy in human lung adenocarcinoma (A549 cells). Food Chem Toxicol 103:28-40. https://doi.org/10.1016/j.fct.2017.02.020
  52. Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y (2018) Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep 39:1523-1531. https://doi.org/10.3892/or.2018.6188