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Tumor Biology

, Volume 37, Issue 6, pp 7599–7613 | Cite as

Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway

  • Xuechao Li
  • Yarong Song
  • Peng Zhang
  • Hongxue Zhu
  • Lifeng Chen
  • Yajun Xiao
  • Yifei Xing
Original Article

Abstract

Oleanolic acid (OA) is a naturally occurring pentacyclic triterpenoid and possesses diverse pharmacological activities, including anti-cancer effects that have been confirmed in multiple types of human cancers. However, the potential effect of natural OA on human prostate cancer is still unclear. The present study aimed to explore whether and how OA exerted anti-cancer effects in prostate cancer. Our data showed that OA inhibited cell viability and proliferation, and promoted cell apoptosis and G0/G1 phase cell cycle arrest in prostate cancer PC-3, DU145, and LNCaP cells, in a dose-dependent manner. In addition, OA was found to regulate the expression levels of apoptosis-related and cell cycle-related proteins, as well as the activity of PI3K/Akt pathway, in a dose-dependent manner. Mechanistically, our data revealed that OA exerted anti-cancer effects in vitro in PC-3 and DU145 cells by repressing the PI3K/Akt pathway. In agreement, OA also suppressed the tumor growth of PC-3 cells in vivo via inhibition of the PI3K/Akt pathway. In conclusion, our findings demonstrate the anti-cancer properties of OA in prostate cancer cells, both in vitro and in vivo, and provide the experimental evidence for the use of OA as an adjuvant agent for prostate cancer patients.

Keywords

Oleanolic acid Prostate cancer Cell survival Proliferation PI3K/Akt pathway 

Notes

Compliance with ethical standards

Funding

This study was funded by the National Natural Science Foundation of China (Nos. 81272847 and 30973008) and the Program for New Century Excellent Talents in University (NCET-13-0239).

Conflicts of interest

None

Statement of human right

This article does not contain any studies with human participants performed by any of the authors.

Ethical approval

This article contains studies with animals. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This study was approved by the Institutional Animal Care and Use Committee of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s. Republic of China (IACUC Number: S430). All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

References

  1. 1.
    Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol. 1995;49:57–68.CrossRefPubMedGoogle Scholar
  2. 2.
    Pollier J, Goossens A. Oleanolic acid. Phytochemistry. 2012;77:10–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Castellano JM, Guinda A, Delgado T, Rada M, Cayuela JA. Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes. Diabetes. 2013;62:1791–9.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sultana N, Ata A. Oleanolic acid and related derivatives as medicinally important compounds. J Enzyme Inhib Med Chem. 2008;23:739–56.CrossRefPubMedGoogle Scholar
  5. 5.
    Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, et al. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep. 2006;23:394–411.CrossRefPubMedGoogle Scholar
  6. 6.
    Allouche Y, Warleta F, Campos M, Sanchez-Quesada C, Uceda M, Beltran G, et al. Antioxidant, antiproliferative, and pro-apoptotic capacities of pentacyclic triterpenes found in the skin of olives on MCF-7 human breast cancer cells and their effects on DNA damage. J Agric Food Chem. 2011;59:121–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Wang X, Bai H, Zhang X, Liu J, Cao P, Liao N, et al. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis. 2013;34:1323–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Shyu MH, Kao TC, Yen GC. Oleanolic acid and ursolic acid induce apoptosis in HuH7 human hepatocellular carcinoma cells through a mitochondrial-dependent pathway and downregulation of XIAP. J Agric Food Chem. 2010;58:6110–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Liese J, Abhari BA, Fulda S. Smac mimetic and oleanolic acid synergize to induce cell death in human hepatocellular carcinoma cells. Cancer Lett. 2015;365:47–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Lucio KA, Rocha Gda G, Moncao-Ribeiro LC, Fernandes J, Takiya CM, Gattass CR. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS ONE. 2011;6:e28596.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhao X, Liu M, Li D. Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis. Mol Cell Biochem. 2015;400:1–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Furtado RA, Rodrigues EP, Araujo FR, Oliveira WL, Furtado MA, Castro MB, et al. Ursolic acid and oleanolic acid suppress preneoplastic lesions induced by 1,2-dimethylhydrazine in rat colon. Toxicol Pathol. 2008;36:576–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Janakiram NB, Indranie C, Malisetty SV, Jagan P, Steele VE, Rao CV. Chemoprevention of colon carcinogenesis by oleanolic acid and its analog in male F344 rats and modulation of COX-2 and apoptosis in human colon HT-29 cancer cells. Pharm Res. 2008;25:2151–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Wei J, Liu M, Liu H, Wang H, Wang F, Zhang Y, et al. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J Appl Toxicol. 2013;33:756–65.CrossRefPubMedGoogle Scholar
  15. 15.
    Wei J, Liu H, Liu M, Wu N, Zhao J, Xiao L, et al. Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep. 2012;28:1339–45.PubMedGoogle Scholar
  16. 16.
    Li HF, Wang XA, Xiang SS, Hu YP, Jiang L, Shu YJ, et al. Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. Drug Des Devel Ther. 2015;9:3017–30.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zhang P, Li H, Chen D, Ni J, Kang Y, Wang S. Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly(ADP-ribose) polymerase cleavage. Acta Biochim Biophys Sin (Shanghai). 2007;39:803–9.CrossRefGoogle Scholar
  18. 18.
    Fujiwara Y, Komohara Y, Kudo R, Tsurushima K, Ohnishi K, Ikeda T, et al. Oleanolic acid inhibits macrophage differentiation into the M2 phenotype and glioblastoma cell proliferation by suppressing the activation of STAT3. Oncol Rep. 2011;26:1533–7.PubMedGoogle Scholar
  19. 19.
    Guo G, Yao W, Zhang Q, Bo Y. Oleanolic acid suppresses migration and invasion of malignant glioma cells by inactivating MAPK/ERK signaling pathway. PLoS ONE. 2013;8:e72079.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Deeb D, Gao X, Dulchavsky SA, Gautam SC. CDDO-me induces apoptosis and inhibits Akt, mTOR and NF-kappaB signaling proteins in prostate cancer cells. Anticancer Res. 2007;27:3035–44.PubMedGoogle Scholar
  21. 21.
    Deeb D, Gao X, Jiang H, Janic B, Arbab AS, Rojanasakul Y, et al. Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. Biochem Pharmacol. 2010;79:350–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Deeb D, Gao X, Liu Y, Jiang D, Divine GW, Arbab AS, et al. Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate cancer in TRAMP mice by inhibiting survival signaling. Carcinogenesis. 2011;32:757–64.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gao X, Deeb D, Liu Y, Arbab AS, Divine GW, Dulchavsky SA, et al. Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer. Cancer. 2011;3:3353–69.CrossRefGoogle Scholar
  24. 24.
    Guo P, Pi H, Xu S, Zhang L, Li Y, Li M, et al. Melatonin improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro. Toxicol Sci. 2014;142:182–95.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Goldman A, Chen H, Khan MR, Roesly H, Hill KA, Shahidullah M, et al. The Na+/H+ exchanger controls deoxycholic acid-induced apoptosis by a H + −activated, Na + −dependent ionic shift in esophageal cells. PLoS ONE. 2011;6, e23835.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li X, Li T, Chen D, Zhang P, Song Y, Zhu H, Xiao Y, Xing Y (2015) Overexpression of lysine-specific demethylase 1 promotes androgen-independent transition of human prostate cancer LNCaP cells through activation of the AR signaling pathway and suppression of the p53 signaling pathway. Oncol RepGoogle Scholar
  27. 27.
    Wang X, Spandidos A, Wang H, Seed B. PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update. Nucleic Acids Res. 2012;40:D1144–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309–12.CrossRefPubMedGoogle Scholar
  29. 29.
    Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6:513–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1–13.CrossRefPubMedGoogle Scholar
  31. 31.
    Reiners Jr JJ, Kleinman M, Kessel D, Mathieu PA, Caruso JA. Nonesterified cholesterol content of lysosomes modulates susceptibility to oxidant-induced permeabilization. Free Radic Biol Med. 2011;50:281–94.CrossRefPubMedGoogle Scholar
  32. 32.
    Franke TF. PI3K/Akt: getting it right matters. Oncogene. 2008;27:6473–88.CrossRefPubMedGoogle Scholar
  33. 33.
    Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455–64.CrossRefPubMedGoogle Scholar
  34. 34.
    Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C, et al. Posttranslational regulation of Akt in human cancer. Cell Biosci. 2014;4:59.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.CrossRefPubMedGoogle Scholar
  36. 36.
    Cassinelli G, Zuco V, Gatti L, Lanzi C, Zaffaroni N, Colombo D, et al. Targeting the Akt kinase to modulate survival, invasiveness and drug resistance of cancer cells. Curr Med Chem. 2013;20:1923–45.CrossRefPubMedGoogle Scholar
  37. 37.
    Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.CrossRefPubMedGoogle Scholar
  38. 38.
    Lowe SW, Lin AW. Apoptosis in cancer. Carcinogenesis. 2000;21:485–95.CrossRefPubMedGoogle Scholar
  39. 39.
    Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–62.CrossRefPubMedGoogle Scholar
  40. 40.
    Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:1126–32.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res. 2011;30:87.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Nicholson DW. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ. 1999;6:1028–42.CrossRefPubMedGoogle Scholar
  43. 43.
    Thornberry NA, Lazebnik Y. Caspases: enemies within. Science. 1998;281:1312–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Salvesen GS, Dixit VM. Caspases: intracellular signaling by proteolysis. Cell. 1997;91:443–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Adams JM, Cory S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci. 2001;26:61–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 2011;21:92–101.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411:342–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Diaz-Moralli S, Tarrado-Castellarnau M, Miranda A, Cascante M. Targeting cell cycle regulation in cancer therapy. Pharmacol Ther. 2013;138:255–71.CrossRefPubMedGoogle Scholar
  49. 49.
    Carnero A. Targeting the cell cycle for cancer therapy. Br J Cancer. 2002;87:129–33.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMedGoogle Scholar
  51. 51.
    Nurse P. Ordering S phase and M phase in the cell cycle. Cell. 1994;79:547–50.CrossRefPubMedGoogle Scholar
  52. 52.
    Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–69.CrossRefPubMedGoogle Scholar
  53. 53.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11:558–72.CrossRefPubMedGoogle Scholar
  54. 54.
    Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Hers I, Vincent EE, Tavare JM. Akt signalling in health and disease. Cell Signal. 2011;23:1515–27.CrossRefPubMedGoogle Scholar
  56. 56.
    Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.CrossRefPubMedGoogle Scholar
  57. 57.
    Testa JR, Bellacosa A. AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A. 2001;98:10983–5.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004;15:177–82.CrossRefPubMedGoogle Scholar
  59. 59.
    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–41.CrossRefPubMedGoogle Scholar
  60. 60.
    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282:1318–21.CrossRefPubMedGoogle Scholar
  61. 61.
    Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2:339–45.CrossRefPubMedGoogle Scholar
  62. 62.
    Takahashi-Yanaga F, Sasaguri T. GSK-3beta regulates cyclin D1 expression: a new target for chemotherapy. Cell Signal. 2008;20:581–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Maiese K, Chong ZZ, Shang YC, Hou J. Clever cancer strategies with FoxO transcription factors. Cell Cycle. 2008;7:3829–39.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Lei H, Quelle FW. FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage. Mol Cancer Res. 2009;7:1294–303.CrossRefPubMedGoogle Scholar
  65. 65.
    van der Horst A, Burgering BM. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 2007;8:440–50.CrossRefPubMedGoogle Scholar
  66. 66.
    Zhang X, Tang N, Hadden TJ, Rishi AK. Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 1813;2011:1978–86.Google Scholar
  67. 67.
    Kloet DE, Burgering BM. The PKB/FOXO switch in aging and cancer. Biochim Biophys Acta. 1813;2011:1926–37.Google Scholar
  68. 68.
    Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2000;275:10761–6.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Xuechao Li
    • 1
  • Yarong Song
    • 1
  • Peng Zhang
    • 1
  • Hongxue Zhu
    • 1
    • 2
  • Lifeng Chen
    • 1
  • Yajun Xiao
    • 1
  • Yifei Xing
    • 1
  1. 1.Department of Urology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of UrologyHospital of Xinjiang Production and Construction CorpsUrumqiChina

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