β-Elemene Induces Apoptosis in Human Renal-cell Carcinoma 786-0 Cells through Inhibition of MAPK/ERK and PI3K/Akt/mTOR Signalling Pathways

  • Zhan, Yun-Hong (Department of Urology, the Shengjing Hospital) ;
  • Liu, Jing (Department of Medical Oncology, the First Hospital, China Medical University) ;
  • Qu, Xiu-Juan (Department of Medical Oncology, the First Hospital, China Medical University) ;
  • Hou, Ke-Zuo (Department of Medical Oncology, the First Hospital, China Medical University) ;
  • Wang, Ke-Feng (Department of Urology, the Shengjing Hospital) ;
  • Liu, Yun-Peng (Department of Medical Oncology, the First Hospital, China Medical University) ;
  • Wu, Bin (Department of Urology, the Shengjing Hospital)
  • Published : 2012.06.30


Background: Renal-cell carcinoma (RCC) is resistant to almost all chemotherapeutics and radiation therapy. ${\beta}$-Elemene, a promising anticancer drug extracted from a traditional Chinese medicine, has been shown to be effective against various tumors. In the present study, anti-tumor effects on RCC cells and the involved mechanisms were investigated. Methods: Human RCC 786-0 cells were treated with different concentrations of ${\beta}$-elemene, and cell viability and apoptosis were measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry, respectively. Protein expression was assayed by western blotting. Autophagy was evaluated by transmission electron microscopy. Results: ${\beta}$-Elemene inhibited the viability of 786-0 cells in a dose- and time-dependent manner. The anti-tumor effect was associated with induction of apoptosis. Further study showed that ${\beta}$-elemene inhibited the MAPK/ERK as well as PI3K/Akt/mTOR signalling pathways. Moreover, robust autophagy was observed in cells treated with ${\beta}$-elemene. Combined treatment of ${\beta}$-elemene with autophagy inhibitors 3-methyladenine or chlorochine significantly enhanced the anti-tumor effects. Conclusions: Our data provide first evidence that ${\beta}$-elemene can inhibit the proliferation of RCC 786-0 cells by inducing apoptosis as well as protective autophagy. The anti-tumor effect was associated with the inhibition of MAPK/ERK and PI3K/Akt/mTOR signalling pathway. Inhibition of autophagy might be a useful way to enhance the anti-tumor effect of ${\beta}$-elemene on 786-0 cells.


  1. Abou Youssif T, Fahmy MA, Koumakpayi IH, et al (2011). The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases. Cancer, 117, 290-300.
  2. Amaravadi RK, Yu D, Lum JJ, et al (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest, 117, 326-36.
  3. Anandappa G, Hollingdale A, Eisen T (2010). Everolimus - a new approach in the treatment of renal cell carcinoma. Cancer Manag Res, 2, 61-70.
  4. Borders EB, Bivona C, Medina PJ (2010). Mammalian target of rapamycin: biological function and target for novel anticancer agents. Am J Health Syst Pharm, 67, 2095-106.
  5. Bullock A, McDermott DF, Atkins MB (2010). Management of metastatic renal cell carcinoma in patients with poor prognosis. Cancer Manag Res, 2, 123-32.
  6. Chen W, Lu Y, Wu J, et al (2011). Beta-elemene inhibits melanoma growth and metastasis via suppressing vascular endothelial growth factor-mediated angiogenesis. Cancer Chemother Pharmacol, 67, 799-808.
  7. Escudier B, Eisen T, Stadler WM, et al (2007). TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 356, 125-34.
  8. Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010). mTOR regulation of autophagy. FEBS Lett, 584, 1287-95.
  9. Li L, Gao Y, Zhang L, et al (2008). Silibinin inhibits cell growth and induces apoptosis by caspase activation, downregulating survivin and blocking EGFR-ERK activation in renal cell carcinoma. Cancer Lett, 272, 61-9.
  10. Lin F, Zhang PL, Yang XJ, et al (2006). Morphoproteomic and molecular concomitants of an overexpressed and activated mTOR pathway in renal cell carcinomas. Ann Clin Lab Sci, 36, 283-93.
  11. Li QQ, Wang G, Huang F, Banda M, Reed E (2010). Antineoplastic effect of beta-elemene on prostate cancer cells and other types of solid tumour cells. J Pharm Pharmacol, 62, 1018-27.
  12. Li QQ, Wang G, Reed E, Huang L, Cuff CF (2010). Evaluation of Cisplatin in Combination with beta-Elemene as a Regimen for Prostate Cancer Chemotherapy. Basic Clin Pharmacol Toxicol, 107, 868-76.
  13. Li QQ, Wang G, Zhang M, et al (2009). beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis. Oncol Rep, 22, 161-70.
  14. Li X, Fan Z (2010). The epidermal growth factor receptor antibody cetuximab induces autophagy in cancer cells by downregulating HIF-1{alpha} and Bcl-2 and activating the beclin 1/hVps34 complex. Cancer Res, 70, 5942-52.
  15. Li X, Wang G, Zhao J, et al (2005). Antiproliferative effect of beta-elemene in chemoresistant ovarian carcinoma cells is mediated through arrest of the cell cycle at the G2-M phase. Cell Mol Life Sci, 62, 894-904.
  16. McDermott DF (2009). Immunotherapy of metastatic renal cell carcinoma. Cancer, 115, 2298-305.
  17. Mizushima N (2008). Autophagy: process and function. Genes Dev, 21, 2861-73.
  18. Motzer RJ, Hutson TE, Tomczak P, et al (2007). Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med, 356, 115-24.
  19. Robb VA, Karbowniczek M, Klein-Szanto AJ, Henske EP (2007). Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol, 177, 346-52.
  20. Sasaki K, Tsuno NH, Sunami E, et al (2010). Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells. BMC Cancer, 10, 370.
  21. Takano Y, Iwata H, Yano Y, et al (2010). Up-regulation of connexin 32 gene by 5-aza-2'-deoxycytidine enhances vinblastine-induced cytotoxicity in human renal carcinoma cells via the activation of JNK signalling. Biochem Pharmacol, 80, 463-70.
  22. Tan P, Zhong W, Cai W, et al (2000). [Clinical study on treatment of 40 cases of malignant brain tumor by elemene emulsion injection]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 20, 645-8. [Article in Chinese]
  23. Thorburn A (2008). Apoptosis and Autophagy: regulatory connections between two supposedly different processes. Apoptosis, 13, 1-9.
  24. Wang G, Li X, Huang F, et al (2005). Antitumor effect of betaelemene in non-small-cell lung cancer cells is mediated via induction of cell cycle arrest and apoptotic cell death. Cell Mol Life Sci, 62, 881-93.
  25. Wang J, Zhang H, Sun Y, et al (1996). Phase III clinical trial of elemenum emulsion in the management of malignant pleural and peritoneal effusions. Zhonghua Zhong Liu Za Zhi, 18, 464-7 (in Chinese).
  26. Weston CR, Lambright DG, Davis RJ (2002). Signal transduction: MAP kinase signaling specificity. Science, 296, 2345-7.
  27. Yang Z, Klionsky DJ (2010). Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol, 22, 124-31.
  28. Yao YQ, Ding X, Jia YC, et al (2008). Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation. Cancer Lett, 264, 127-34.
  29. Zhu K, Dunner K Jr, McConkey DJ (2010). Proteasome inhibitors activate autophagy as a cytoprotective response in human prostate cancer cells. Oncogene, 29, 451-62.
  30. Zhu T, Zhao Y, Zhang J, et al (2011). $\beta$-Elemene inhibits proliferation of human glioblastoma cells and causes cellcycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. Int J Oncol, 38, 419-26.

Cited by

  1. The Role of E3 Ubiquitin Ligase Cbl Proteins in β-Elemene Reversing Multi-Drug Resistance of Human Gastric Adenocarcinoma Cells vol.14, pp.5, 2013,
  2. ADAM17 is a survival factor for microglial cells in vitro and in vivo after spinal cord injury in mice vol.4, pp.12, 2013,
  3. Autophagy in Kidney Health and Disease vol.20, pp.3, 2014,
  4. Down regulation of mammalian target of rapamycin decreases HIF-1α and survivin expression in anoxic lung adenocarcinoma A549 cell to elemene and/or irradiation vol.35, pp.10, 2014,
  5. Future perspectives for mTOR inhibitors in renal cell cancer treatment vol.11, pp.5, 2015,
  6. MicroRNA-148b enhances proliferation and apoptosis in human renal cancer cells via directly targeting MAP3K9 vol.13, pp.1, 2015,
  7. Natural autophagy regulators in cancer therapy: a review vol.14, pp.1, 2015,
  8. β-elemene Induces Caspase-dependent Apoptosis in Human Glioma Cells in vitro through the Upregulation of Bax and Fas/FasL and Downregulation of Bcl-2 vol.15, pp.23, 2015,
  9. β-elemene inhibited expression of DNA methyltransferase 1 through activation of ERK1/2 and AMPKα signalling pathways in human lung cancer cells: the role of Sp1 vol.19, pp.3, 2015,
  10. -terminal Kinase Phosphorylation vol.30, pp.2, 2015,
  11. Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O vol.36, pp.2, 2015,
  12. CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells vol.20, pp.2, 2016,
  13. Volatile constituents of Distichochlamys citrea M. F. Newman and Distichochlamys orlowii K. Larsen M. F. Newman (Zingiberaceae) from Vietnam vol.11, pp.9, 2017,
  14. A Case of Recurrent Hepatocellular Carcinoma Acquiring Complete Remission of Target Lesion With Treatment With Traditional Chinese Medicine vol.16, pp.4, 2017,
  15. vol.20, pp.1, 2017,
  16. Synergistic Cytotoxicity of β-Elemene and Cisplatin in Gingival Squamous Cell Carcinoma by Inhibition of STAT3 Signaling Pathway vol.23, pp.1643-3750, 2017,
  17. H. Baillon bark essential oil vol.152, pp.1, 2018,
  18. Composition and potential anticancer activities of essential oils obtained from myrrh and frankincense vol.6, pp.4, 2013,
  19. Anticancer effects of β-elemene in gastric cancer cells and its potential underlying proteins: A proteomic study vol.32, pp.6, 2014,
  20. β-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway vol.49, pp.4, 2016,
  21. Depletion of the triggering receptor expressed on myeloid cells 2 inhibits progression of renal cell carcinoma via regulating related protein expression and PTEN-PI3K/Akt pathway vol.49, pp.6, 2016,
  22. The O-methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation vol.119, pp.9, 2018,
  23. Non-Curcuminoids from Turmeric and Their Potential in Cancer Therapy and Anticancer Drug Delivery Formulations vol.9, pp.1, 2019,