Journal of Physiology & Pathology in Korean Medicine (동의생리병리학회지)

The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine (대한동의생리학회·한의병리학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of Adrenergic Agonists-induced Metastatic Ability of Liver Cancer Cells by Ethanol Extract of Premature Citrus Unshiu Peel

청피 에탄올 추출물이 스트레스성 카테콜아민으로 유도한 간암세포의 전이를 억제하는 효과 및 기전 연구

  • Shin-Hyung Park (Department of Pathology, College of Korean Medicine, Dong-eui University)
  • 박신형 (동의대학교 한의과대학 병리학교실)
  • Received : 2023.12.12
  • Accepted : 2024.02.13
  • Published : 2024.02.25
Download PDF
⟨ Previous Next ⟩

Abstract

Previous studies have highlighted the pivotal role of the β-adrenergic receptor (β-AR) signaling pathway in stimulating cancer metastasis induced by chronic stress. According to the theory of traditional Korean medicine, chronic stress can induce Qi stagnation. Based on the traditional role of premature citrus unshiu peel in moving Qi, we hypothesized that an ethanol extract of premature citrus unshiu peel (EPCU) can attenuate chronic stress-induced cancer progression. In this study, we investigated the potential role of EPCU on modulating the adrenergic agonists-induced metastatic properties of liver cancer cells. Our findings revealed that adrenergic agonists, including norepinephrine (NE), epinephrine (E), and isoproterenol (ISO), augmented the migratory capacity of Hep3B human hepatocellular carcinoma cells, which was completely abrogated by EPCU treatment in a concentration-dependent manner. Consistently, EPCU inhibited the E-induced invasive property of Hep3B cells in a dose-dependent manner. These results suggest that EPCU efficiently attenuates adrenergic agonists-induced metastatic abilities of liver cancer cells. As a molecular mechanism, EPF suppressed the phosphorylation of major components of β-AR signaling pathway, including Src, signal transducer and activator of transcription 3 (STAT3) and ERK, induced by E treatment. Taken together, our results demonstrate that EPCU impedes the adrenergic agonists-driven metastatic potential of cancer cells by inhibiting β-AR signaling pathway. This study provides basic evidence supporting the probable use of premature citrus unshiu peel to prevent metastasis in liver cancer patients under chronic stress.

Keywords

Acknowledgement

본 연구는 한국연구재단의 우수신진연구의 사업비로 수행되었음(No. NRF-2021R1C1C100506211).

References

  1. Oh HM, Son CG. The Risk of Psychological Stress on Cancer Recurrence: A Systematic Review. Cancers 2021;13:5816. https://doi.org/10.3390/cancers13225816
  2. Batty GD, Russ TC, Stamatakis E, Kivimaki M. Psychological distress in relation to site specific cancer mortality: Pooling of unpublished data from 16 prospective cohort studies. BMJ 2017;356:j108.
  3. Kim-Fuchs C, Le CP, Pimentel MA, Shackleford D, Ferrari D, Angst E, Hollande F, Sloan EK. Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 2014;40:40-7. https://doi.org/10.1016/j.bbi.2014.02.019
  4. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 2006;12:939-44. https://doi.org/10.1038/nm1447
  5. Chang A, Le CP, Walker AK, Creed, SJ, Pon CK, Albold S, et al. 2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav. Immun. 2016;57:106-15. https://doi.org/10.1016/j.bbi.2016.06.011
  6. Gudenkauf LM, Ehlers SL. Psychosocial interventions in breast cancer survivorship care. Breast 2018;38:1-6. https://doi.org/10.1016/j.breast.2017.11.005
  7. Fawzy FI, Fawzy NW, Hyun CS, Elashoff R, Guthrie D, Fahey JL, et al. Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later. Arch. Gen. Psychiatry 1993;50:681-9. https://doi.org/10.1001/archpsyc.1993.01820210015002
  8. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5:617-25. https://doi.org/10.1016/S1470-2045(04)01597-9
  9. Cole SW, Sood AK. Molecular pathways: Beta-adrenergic signaling in cancer. Clin. Cancer Res. 2012;18:1201-1206. https://doi.org/10.1158/1078-0432.CCR-11-0641
  10. Mravec B, Horvathova L, Hunakova L. Neurobiology of Cancer: the Role of β-Adrenergic Receptor Signaling in Various Tumor Environments. Int. J. Mol. Sci. 2020;21(21):7958.
  11. Cui B, Peng F, Lu J, He B, Su Q, Luo H, et al. Cancer and stress: NextGen strategies. Brain Behav. Immun. 2021;93:368-83. https://doi.org/10.1016/j.bbi.2020.11.005
  12. Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F. et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 2011;29:2645-52. https://doi.org/10.1200/JCO.2010.33.4441
  13. Parada-Huerta E, Alvarez-Dominguez T, Uribe-Escamilla R, Rodriguez-Joya J, Ponce-Medrano JD, Padron-Lucio S, et al. Metastasis Risk Reduction Related with Beta-Blocker Treatment in MexicanWomen with Breast Cancer. Asian Pac. J. Cancer Prev. 2016;17:2953-7.
  14. Udumyan R, Montgomery S, Fang F, Almroth H, Valdimarsdottir U, Ekbom A, et al. Beta-Blocker Drug Use and Survival among Patients with Pancreatic Adenocarcinoma. Cancer Res. 2017;77:3700-7. https://doi.org/10.1158/0008-5472.CAN-17-0108
  15. National Cancer Information Center. https://www.cancer.go.kr/
  16. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48. https://doi.org/10.3322/caac.21763
  17. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim. Biophys. Acta. Rev. Cancer 2020;1873(1):188314.
  18. The Jointly Published Textbook Compilation Committee of Oriental College of Medicine Nationwide Department. Herbology. Seoul: Younglim press; 2004.
  19. Ye YJ, Kim YS, Kang Ms. Effects of Citri Reticulatae Viride Pericarpium on 4-Hydroxynonenal-Induced Inflammation in PC12 Cells. J. Kor. Med. Obes. Res. 2016;16:79-84. https://doi.org/10.15429/jkomor.2016.16.2.79
  20. Lee HJ. Effectiveness of Citri Reticulatae Viride Pericarpium in the Bronchial Asthma Animal Model: Assessment on the vascular endothelial growth factor (VEGF). Kor. J. Ori. Med. Physiol. Pathol. 2003; 17(6):1475-8.
  21. Yang SG, Park HS. Effects of Aqua-acupuncture with Chungpi on CCI4-induced Rat's Liver Injury. J. Acupunct. Res. 1998;15(1):431-45.
  22. Lee WS, Jeong HW. Experimental Effects of Fraction of Citri Reticulatae Viride Pericarpium extract on the Cerebral Hemodynamics in Cerebral Ischemia Pathologic-Modeling Rats. Kor. J. Ori. Med. Physiol. Pathol. 2001;15(6):899-904.
  23. Kwon YW, Lee TH. Antidepressant Effects of Citri Reticulatae Viride Pericarpium in the Forced Swimming Test. Kor. J. Herbology 2003;23(4):59-70.
  24. Kim JE, Park SY, Choi CW, Kim KS, Kim KO, Wei TS, et al. Effects of Citri Reticulatae Viride Pericarpium on the Apoptotic Cell Death in Breast Cancer Cells. Kor. J. Obstet. Gynecol. 2015;28(2):40-54.
  25. Lee SY. Apoptotic effect of herbal-acupuncture solution of Citri Reticulatae Viride Pericarpium in SNU-C4, human colon cancer cell. Master's Thesis at Daegu Haany University. 2004.
  26. Kim MS. Effects of Citrus Reticulata on the Cell Detachment and Apoptosis in Human Gastric Cancer SNU-668 Cells. Doctoral Thesis at Semyung University. 2005.
  27. The Textbook Compilation Committee of Pathology of Korean Medicine. Pathology of Korean Medicine. Seoul: Hanimunhwasa; 2019.
  28. Cho JK. Oriental Clinical Oncology. Daejeon: Jumin Publishing House; 2005.
  29. Jeong JH, Park HJ, Park SH, Choi YH, Chi GY. β2-Adrenergic Receptor Signaling Pathway Stimulates the Migration and Invasion of Cancer Cells via Src Activation. Molecules 2022;27(18):5940.
  30. Liang F, Sun J, Zhang Y, Han JH, Xu J. Liver Qi Stagnation-emotion Pathopoiesis and Malignant Tumor. J. Prac. Trad. Chin. Int. Med. 2016;30(5):42-4.
  31. Chen Z, Hou F, Sun K. Literature analysis of TCM syndromes of liver cancer. J. Anhui. TCM College 2002;21(2):24-26.
  32. Yuan A, Li Z, Li X, Yi S, Wang S, Cai Y, et al. The mitogenic effectors of isoproterenol in human hepatocellular carcinoma cells. Oncol Rep. 2010;23(1):151-7. https://doi.org/10.3892/or_00000616
  33. Udumyan R, Montgomery S, Duberg AS, Fang F, Valdimarsdottir U, Ekbom A, et al. Beta-adrenergic receptor blockers and liver cancer mortality in a national cohort of hepatocellular carcinoma patients. Scand. J. Gastroenterol. 2020;55(5):597-605. https://doi.org/10.1080/00365521.2020.1762919
  34. Choi EO, Lee H, HwangBo H, Kwon DH, Kim MY, Ji SY, et al. Citrus unshiu peel suppress the metastatic potential of murine melanoma B16F10 cells in vitro and in vivo. Phytother. Res. 2019;33(12):3228-41. https://doi.org/10.1002/ptr.6497
  35. Lee J, Lee J, Kim M, Kim JH. Fermented Extraction of Citrus unshiu Peel Inhibits Viability and Migration of Human Pancreatic Cancers. J. Med. Food. 2018;21(1):5-12. https://doi.org/10.1089/jmf.2017.3984
  36. Zhang S, Yu D. Targeting Src family kinases in anticancer therapies: Turning promise into triumph. Trends Pharmacol. Sci. 2012;33:122-8.
  37. Liu X, Feng R. Inhibition of epithelial to mesenchymal transition in metastatic breast carcinoma cells by c-Src suppression. Acta. Biochim. Biophys. Sin. 2010;42:496-501. https://doi.org/10.1093/abbs/gmq043
  38. El-Tanani M, Al Khatib AO, Aladwan SM, Abuelhana A, McCarron PA, Tambuwala MM. Importance of STAT3 signalling in cancer, metastasis and therapeutic interventions. Cell Signal. 2022;92:110275.
  39. Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp. Ther. Med. 2020;19(3):1997-2007.
  40. Aggarwal V, Tuli HS, Thakral F, Singhal P, Aggarwal D, Srivastava S, et al. Molecular mechanisms of action of hesperidin in cancer: Recent trends and advancements. Exp Biol Med (Maywood). 2020;245(5):486-97. https://doi.org/10.1177/1535370220903671
  41. Kottaiswamy A, Kizhakeyil A, Padmanaban AM, Mirza FB, Vijay VR, Lee PS, et al. The Citrus Flavanone Hesperetin Induces Apoptosis in CTCL Cells via STAT3/Notch1/NFκB-Mediated Signaling Axis. Anticancer Agents Med. Chem. 2020;20(12):1459-68. https://doi.org/10.2174/1871521409666200324110031
  42. Araujo-Filho HG, Dos Santos JF, Carvalho MTB, Picot L, Fruitier-Arnaudin I, Groult H, et al Anticancer activity of limonene: A systematic review of target signaling pathways. Phytother Res. 2021;35(9):4957-70.  https://doi.org/10.1002/ptr.7125