The Journal of Physiological Sciences

, Volume 69, Issue 2, pp 185–198 | Cite as

Matrine has pro-apoptotic effects on liver cancer by triggering mitochondrial fission and activating Mst1-JNK signalling pathways

  • Jian Cao
  • Runjie Wei
  • Shukun YaoEmail author
Original Paper


Mitochondrial homeostasis is closely associated with liver cancer progression via multiple mechanisms and is also a potential tumour-suppressive target in clinical practice. However, the role of mitochondrial fission in liver cancer cell viability has not been adequately investigated. Matrine, a type of alkaloid isolated from Sophoraflavescens, has been widely used to treat various types of cancer. However, the molecular effect of matrine on mitochondrial homeostasis is unclear. Therefore, the aim of the current study was to determine the role of mitochondrial fission in cell apoptosis, viability, migration and proliferation of HepG2 cells in vitro. The effect of matrine on mitochondrial fission and its mechanism were also explored. The results of our study showed that HepG2 cells treated with matrine had reduced viability, an increased apoptotic rate, a blunted migratory response, and impaired proliferation capacity. At the molecular level, matrine treatment activated mitochondrial fission, which promoted mitochondrial dysfunction, caused cellular oxidative stress, disrupted cellular energy metabolism and initiated cell apoptotic pathways. However, blockade of mitochondrial fission abolished the deleterious effects of matrine on HepG2 cells. Further, we demonstrated that the Mst1-JNK signalling axis was required for matrine-modulated mitochondrial fission. Matrine-mediated mitochondrial dysfunction was reversed by inhibiting Mst1-JNK pathways. Together, our results demonstrated that mitochondrial fission could be a potential upstream tumour-suppressive signal for liver cancer by modifying mitochondrial function and cell death. By contrast, matrine exerted an anticancer function in liver cancer by activating mitochondrial fission mediated by Mst1-JNK pathways.


Matrine Mitochondrial fission Mst1-JNK pathways Liver cancer Apoptosis 


Author contributions

CJ and SKY conceived the research; RJW, CJ and SKY performed the experiments; all authors participated in discussing and revising the manuscript.


This study was funded in full by the Leap-forward Development Program for Beijing Biopharmaceutical Industry (G20), Grant Number Z171100001717008.

Compliance with ethical standards

Conflict of interest

Not applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article.


  1. 1.
    Jiang JH, Pi J, Jin H, Yang F, Cai JY (2018) Chinese herb medicine matrine induce apoptosis in human esophageal squamous cancer KYSE-150 cells through increasing reactive oxygen species and inhibiting mitochondrial function. Pathol Res Pract 214:691–699CrossRefGoogle Scholar
  2. 2.
    Takeya M, Okumura Y, Nikawa T (2017) Modulation of cutaneous extracellular collagen contraction by phosphorylation status of p130Cas. J Physiol Sci 67:613–622CrossRefGoogle Scholar
  3. 3.
    Oyama Y, Iigaya K, Minoura Y, Okabe T, Izumizaki M, Onimaru H (2017) An in vitro experimental model for analysis of central control of sympathetic nerve activity. J Physiol Sci 67:629–635CrossRefGoogle Scholar
  4. 4.
    Thirusangu P, Vigneshwaran V, Prashanth T, Vijay Avin BR, Malojirao VH, Rakesh H, Khanum SA, Mahmood R, Prabhakar BT (2017) BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1alpha proteasomal degradation. Angiogenesis 20:55–71CrossRefGoogle Scholar
  5. 5.
    Liu Z, Gan L, Luo D, Sun C (2017) Melatonin promotes circadian rhythm-induced proliferation through Clock/histone deacetylase 3/c-Myc interaction in mouse adipose tissue. J Pineal Res 62:e12383CrossRefGoogle Scholar
  6. 6.
    Shin D, Kim EH, Lee J, Roh JL (2017) RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems. Redox Biol 13:219–227CrossRefGoogle Scholar
  7. 7.
    Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J, Chen Y (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol 113:23CrossRefGoogle Scholar
  8. 8.
    Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, Ma Q, Tian F, Chen Y (2017) Mff-dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROS-mediated cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc 6:e005328Google Scholar
  9. 9.
    Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J (2018) Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res 64:e12450CrossRefGoogle Scholar
  10. 10.
    Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y (2018) BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis 21:599–615CrossRefGoogle Scholar
  11. 11.
    Zhou H, Li D, Zhu P, Ma Q, Toan S, Wang J, Hu S, Chen Y, Zhang Y (2018) Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury. J Pineal Res 65:e12503CrossRefGoogle Scholar
  12. 12.
    Zhou H, Wang S, Hu S, Chen Y, Ren J (2018) ER-mitochondria microdomains in cardiac ischemia-reperfusion injury: a fresh perspective. Front Physiol. 9:755CrossRefGoogle Scholar
  13. 13.
    Lee HJ, Jung YH, Choi GE, Ko SH, Lee SJ, Lee SH, Han HJ (2017) BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol 13:426–443CrossRefGoogle Scholar
  14. 14.
    Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y (2018) Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy. J Pineal Res 64:e12471CrossRefGoogle Scholar
  15. 15.
    Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J, Zhou H (2018) DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol 14:576–587CrossRefGoogle Scholar
  16. 16.
    Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W, Zhou H (2018) Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/CaMKII pathways. Redox Biol 14:59–71CrossRefGoogle Scholar
  17. 17.
    Garcia-Ruiz JM, Galan-Arriola C, Fernandez-Jimenez R, Aguero J, Sanchez-Gonzalez J, Garcia-Alvarez A, Nuno-Ayala M, Dube GP, Zafirelis Z, Lopez-Martin GJ, Bernal JA, Lara-Pezzi E, Fuster V, Ibanez B (2017) Bloodless reperfusion with the oxygen carrier HBOC-201 in acute myocardial infarction: a novel platform for cardioprotective probes delivery. Basic Res Cardiol. 112:17CrossRefGoogle Scholar
  18. 18.
    Rossello X, Yellon DM (2017) The RISK pathway and beyond. Basic Res Cardiol 113:2CrossRefGoogle Scholar
  19. 19.
    Couto JA, Ayturk UM, Konczyk DJ, Goss JA, Huang AY, Hann S, Reeve JL, Liang MG, Bischoff J, Warman ML, Greene AK (2017) A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis 20:303–306CrossRefGoogle Scholar
  20. 20.
    Liu D, Zeng X, Li X, Mehta JL, Wang X (2017) Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res Cardiol 113:5CrossRefGoogle Scholar
  21. 21.
    Ackermann M, Kim YO, Wagner WL, Schuppan D, Valenzuela CD, Mentzer SJ, Kreuz S, Stiller D, Wollin L, Konerding MA (2017) Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis 20:359–372CrossRefGoogle Scholar
  22. 22.
    Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS (2017) Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J Pineal Res 62:e12404CrossRefGoogle Scholar
  23. 23.
    Garcia-Nino WR, Correa F, Rodriguez-Barrena JI, Leon-Contreras JC, Buelna-Chontal M, Soria-Castro E, Hernandez-Pando R, Pedraza-Chaverri J, Zazueta C (2017) Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol 112:15CrossRefGoogle Scholar
  24. 24.
    Fukumoto M, Kondo K, Uni K, Ishiguro T, Hayashi M, Ueda S, Mori I, Niimi K, Tashiro F, Miyazaki S, Miyazaki JI, Inagaki S, Furuyama T (2018) Tip-cell behavior is regulated by transcription factor FoxO1 under hypoxic conditions in developing mouse retinas. Angiogenesis 21:203–214CrossRefGoogle Scholar
  25. 25.
    Pickard JM, Burke N, Davidson SM, Yellon DM (2017) Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning. Basic Res Cardiol 112:11CrossRefGoogle Scholar
  26. 26.
    Blackburn NJR, Vulesevic B, Mcneill B, Cimenci CE, Ahmadi A, Gonzalez-Gomez M, Ostojic A, Zhong Z, Brownlee M, Beisswenger PJ, Milne RW, Suuronen EJ (2017) Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction. Basic Res Cardiol 112:57CrossRefGoogle Scholar
  27. 27.
    Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, Zhang Y, Han T, Ren J, Cao F, Chen Y (2017) Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARgamma/FUNDC1/mitophagy pathways. J Pineal Res 63:e12438CrossRefGoogle Scholar
  28. 28.
    Zhou H, Zhu P, Wang J, Zhu H, Ren J, Chen Y (2018) Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ 25:1080–1093CrossRefGoogle Scholar
  29. 29.
    Alghanem AF, Wilkinson EL, Emmett MS, Aljasir MA, Holmes K, Rothermel BA, Simms VA, Heath VL, Cross MJ (2017) RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis 20:341–358CrossRefGoogle Scholar
  30. 30.
    Feng D, Wang B, Wang L, Abraham N, Tao K, Huang L, Shi W, Dong Y, Qu Y (2017) Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res 62:e12395CrossRefGoogle Scholar
  31. 31.
    Chang SH, Yeh YH, Lee JL, Hsu YJ, Kuo CT, Chen WJ (2017) Transforming growth factor-beta-mediated CD44/STAT3 signaling contributes to the development of atrial fibrosis and fibrillation. Basic Res Cardiol 112:58CrossRefGoogle Scholar
  32. 32.
    Xiao L, Xu X, Zhang F, Wang M, Xu Y, Tang D, Wang J, Qin Y, Liu Y, Tang C, He L, Greka A, Zhou Z, Liu F, Dong Z, Sun L (2017) The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biol 11:297–311CrossRefGoogle Scholar
  33. 33.
    Zhou H, Wang J, Zhu P, Hu S, Ren J (2018) Ripk3 regulates cardiac microvascular reperfusion injury: the role of IP3R-dependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal 45:12–22CrossRefGoogle Scholar
  34. 34.
    Lee HY, Back K (2017) Melatonin is required for H2O2- and NO-mediated defense signaling through MAPKKK3 and OXI1 in Arabidopsis thaliana. J Pineal Res 62:e12379CrossRefGoogle Scholar
  35. 35.
    Yang G, Zhang X, Weng X, Liang P, Dai X, Zeng S, Xu H, Huan H, Fang M, Li Y, Xu D, Xu Y (2017) SUV39H1 mediated SIRT1 trans-repression contributes to cardiac ischemia-reperfusion injury. Basic Res Cardiol 112:22CrossRefGoogle Scholar
  36. 36.
    Zhou H, Yue Y, Wang J, Ma Q, Chen Y (2018) Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal 47:88–100CrossRefGoogle Scholar
  37. 37.
    Hu Z, Cheng J, Xu J, Ruf W, Lockwood CJ (2017) Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy. Angiogenesis. 20:85–96CrossRefGoogle Scholar
  38. 38.
    Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, Coscoy L, Winoto A (2017) Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway. Cell Death Differ 24:615–625CrossRefGoogle Scholar
  39. 39.
    Li R, Xin T, Li D, Wang C, Zhu H, Zhou H (2018) Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol 18:229–243CrossRefGoogle Scholar
  40. 40.
    Jepsen P, Kissmeyer-Nielsen P (2008) Epidemiology of primary and secondary liver cancers. Ugeskr Laeger 170:1323–1325Google Scholar
  41. 41.
    Zhu P, Hu S, Jin Q, Li D, Tian F, Toan S, Li Y, Zhou H, Chen Y (2018) Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: A mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol. 16:157–168CrossRefGoogle Scholar
  42. 42.
    Miranda-Vizuete A, Veal EA (2017) Caenorhabditis elegans as a model for understanding ROS function in physiology and disease. Redox Biol 11:708–714CrossRefGoogle Scholar
  43. 43.
    Ligeza J, Marona P, Gach N, Lipert B, Miekus K, Wilk W, Jaszczynski J, Stelmach A, Loboda A, Dulak J, Branicki W, Rys J, Jura J (2017) MCPIP1 contributes to clear cell renal cell carcinomas development. Angiogenesis 20:325–340CrossRefGoogle Scholar
  44. 44.
    Nauta TD, Van Den Broek M, Gibbs S, Van Der Pouw-Kraan TC, Oudejans CB, Van Hinsbergh VW, Koolwijk P (2017) Identification of HIF-2alpha-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis 20:39–54CrossRefGoogle Scholar
  45. 45.
    Akin S, Naito H, Ogura Y, Ichinoseki-Sekine N, Kurosaka M, Kakigi R, Demirel HA (2017) Short-term treadmill exercise in a cold environment does not induce adrenal Hsp72 and Hsp25 expression. J Physiol Sci. 67:407–413CrossRefGoogle Scholar
  46. 46.
    Kang PT, Chen CL, Lin P, Chilian WM, Chen YR (2017) Impairment of pH gradient and membrane potential mediates redox dysfunction in the mitochondria of the post-ischemic heart. Basic Res Cardiol 112:36CrossRefGoogle Scholar
  47. 47.
    Maezawa T, Tanaka M, Kanazashi M, Maeshige N, Kondo H, Ishihara A, Fujino H (2017) Astaxanthin supplementation attenuates immobilization-induced skeletal muscle fibrosis via suppression of oxidative stress. J Physiol Sci 67:603–611CrossRefGoogle Scholar
  48. 48.
    Yang Y, Guo JX, Shao ZQ, Gao JP (2017) Matrine inhibits bladder cancer cell growth and invasion in vitro through PI3 K/AKT signaling pathway: an experimental study. Asian Pac J Trop Med 10:515–519CrossRefGoogle Scholar
  49. 49.
    Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J (2018) Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol 15:335–346CrossRefGoogle Scholar
  50. 50.
    Rienks M, Carai P, Bitsch N, Schellings M, Vanhaverbeke M, Verjans J, Cuijpers I, Heymans S, Papageorgiou A (2017) Sema3A promotes the resolution of cardiac inflammation after myocardial infarction. Basic Res Cardiol. 112:42CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Biological Science and Medical EngineeringBeihang UniversityBeijingChina
  2. 2.Peking University China-Japan Friendship School of Clinical MedicineBeijingChina
  3. 3.Department of GastroenterologyChina-Japan Friendship HospitalBeijingChina

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