Activation of AMP-activated protein kinase and phosphorylation of glycogen synthase kinase3 β mediate ursolic acid induced apoptosis in HepG2 liver cancer cells

Phytotherapy Research

Volumn 27, Issue 11, 2013, Pages 1714-1722

  Son, Hyun Soo ^a   Kwon, Hee Young ^a   Sohn, Eun Jung ^a   Lee, Jang Hoon ^a   Woo, Hong Jung ^a   Yun, Miyong ^a   Kim, Sung Hoon ^a   Kim, Young Chul ^a  

^a Kyung Hee University   (South Korea)

Author keywords

AMPK; apoptosis; GSK3 ; HepG2 cells; ursolic acid

Indexed keywords

2 (2,4 DICHLOROPHENYL) 3 (1 METHYL 3 INDOLYL)MALEIMIDE; ACYL COENZYME A; ASTROCYTE ELEVATED GENE; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; CASPASE 3; DNA NUCLEOTIDYLEXOTRANSFERASE; GLYCOGEN SYNTHASE KINASE 3BETA; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; MAMMALIAN TARGET OF RAPAMYCIN; NERVE GROWTH FACTOR; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROTEIN KINASE B; SERINE; SURVIVIN; UNCLASSIFIED DRUG; URSOLIC ACID;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL; CANCER INHIBITION; CELL CYCLE; CONTROLLED STUDY; DRUG CYTOTOXICITY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; FLOW CYTOMETRY; HUMAN; HUMAN CELL; LIVER CANCER; NICK END LABELING; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEIN FUNCTION; SIGNAL TRANSDUCTION; UBIQUITINATION; UPREGULATION; WESTERN BLOTTING;

AMPK; APOPTOSIS; GSK3Β; HEPG2 CELLS; URSOLIC ACID;

AMP-ACTIVATED PROTEIN KINASES; APOPTOSIS; CARCINOMA, HEPATOCELLULAR; CASPASE 3; CELL ADHESION MOLECULES; GLYCOGEN SYNTHASE KINASE 3; HEP G2 CELLS; HUMANS; INDOLES; LEUPEPTINS; LIVER NEOPLASMS; MALEIMIDES; PHOSPHORYLATION; POLY(ADP-RIBOSE) POLYMERASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; TOR SERINE-THREONINE KINASES; TRITERPENES; UBIQUITINATION;

EID: 84886303030     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.4925     Document Type: Article

References (57)

1. Baffy G, Brunt EM, Caldwell SH,. 2012. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56: 1384-1391.
2. Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, et al,. 2007. Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. J Androl 28: 282-293.
3. Benzler J, Ganjam GK, Kruger M, et al,. 2012. Hypothalamic glycogen synthase kinase 3beta has a central role in the regulation of food intake and glucose metabolism. Biochem J 447: 175-184.
4. Chen S, Xiao X, Feng X, et al,. 2011. Resveratrol induces Sirt1-dependent apoptosis in 3T3-L1 preadipocytes by activating AMPK and suppressing AKT activity and survivin expression. J Nutr Biochem 23: 1100-1112.
5. Devoy A, Soane T, Welchman R, et al,. 2005. The ubiquitin-proteasome system and cancer. Essays Biochem 41: 187-203.
6. Dowling RJ, Zakikhani M, Fantus IG, et al,. 2007. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67: 10804-10812.
7. Eldridge AG, O'Brien T,. 2009. Therapeutic strategies within the ubiquitin proteasome system. Cell Death Differ 17: 4-13.
8. Fediuc S, Gaidhu MP, Ceddia RB,. 2006. Inhibition of insulin-stimulated glycogen synthesis by 5-aminoimidasole-4-carboxamide-1-beta- d -ribofuranoside-induced adenosine 5′-monophosphate-activated protein kinase activation: interactions with Akt, glycogen synthase kinase 3-3alpha/beta, and glycogen synthase in isolated rat soleus muscle. Endocrinology 147: 5170-5177.
9. Hardie DG,. 2008. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond) 32 (Suppl 4): S7-S12.
10. Hedgepeth CM, Conrad LJ, Zhang J, et al,. 1997. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol 185: 82-91.
11. Hernandez-Davies JE, Zape JP, Landaw EM, et al,. 2011. The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3beta-dependent pathway. Mol Cancer Ther 10: 949-959.
12. Hsu YL, Kuo PL, Lin CC,. 2004. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci 75: 2303-2316.
13. Huang XY, Wang L, Huang ZL, et al,. 2009. Herbal extract "Songyou Yin" inhibits tumor growth and prolongs survival in nude mice bearing human hepatocellular carcinoma xenograft with high metastatic potential. J Cancer Res Clin Oncol 135: 1245-1255.
14. Hughes K, Nikolakaki E, Plyte SE, et al,. 1993. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12: 803-808.
15. Hwang JT, Ha J, Park OJ,. 2005. Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem Biophys Res Commun 332: 433-440.
16. Ikeda Y, Murakami A, Ohigashi H,. 2008. Ursolic acid: an anti- and pro-inflammatory triterpenoid. Mol Nutr Food Res 52: 26-42.
17. Inoki K, Zhu T, Guan KL,. 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577-590.
18. Jia Y, Bhuiyan MJ, Jun HJ, et al,. 2011. Ursolic acid is a PPAR-alpha agonist that regulates hepatic lipid metabolism. Bioorg Med Chem Lett 21: 5876-5880.
19. Kang LJ, Lee HB, Bae HJ, et al,. 2010. Antidiabetic effect of propolis: reduction of expression of glucose-6-phosphatase through inhibition of Y279 and Y216 autophosphorylation of GSK-3alpha/beta in HepG2 cells. Phytother Res 24: 1554-1561.
20. Kassi E, Papoutsi Z, Pratsinis H, et al,. 2007. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J Cancer Res Clin Oncol 133: 493-500.
21. Kefas BA, Cai Y, Ling Z, et al,. 2003. AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase. J Mol Endocrinol 30: 151-161.
22. Kimura N, Tokunaga C, Dalal S, et al,. 2003. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8: 65-79.
23. Kockeritz L, Doble B, Patel S, et al,. 2006. Glycogen synthase kinase-3-an overview of an over-achieving protein kinase. Curr Drug Targets 7: 1377-1388.
24. Lei P, Ayton S, Bush AI, et al,. 2011. GSK-3 in neurodegenerative diseases. Int J Alzheimers DOI: 10.4061/2011/189246.
25. Li Y, Martin RC,. 2011. Herbal medicine and hepatocellular carcinoma: applications and challenges. Evid Based Complement Alternat Med. Article ID 541209, DOI: 10.1093/ecam/neq044.
26. Li J, Liang X, Yang X,. 2012. Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant human pancreatic cancer via the JNK and PI3K/Akt/NF-kappaB pathways. Oncol Rep 28: 501-510.
27. Loberg RD, Vesely E, Brosius FC,. 2002. Enhanced glycogen synthase kinase-3beta activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism. J Biol Chem 277: 41667-41673.
28. Mantovani J, Roy R,. 2010. Re-evaluating the general(ized) roles of AMPK in cellular metabolism. FEBS Lett 585: 967-972.
29. Meisse D, Van de Casteele M, Beauloye C, et al,. 2002. Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells. FEBS Lett 526: 38-42.
30. Mertens-Talcott SU, Percival SS,. 2005. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett 218: 141-151.
31. Metcalfe C, Bienz M,. 2011. Inhibition of GSK3 by Wnt signalling - two contrasting models. J Cell Sci 124: 3537-3544.
32. Motoshima H, Goldstein BJ, Igata M, et al,. 2006. AMPK and cell proliferation-AMPK as a therapeutic target for atherosclerosis and cancer. J Physiol 574: 63-71.
33. Saaby L, Jager AK, Moesby L, et al,. 2011. Isolation of immunomodulatory triterpene acids from a standardized rose hip powder (Rosa canina L.). Phytother Res 25: 195-201.
34. Satomi Y, Nishino H, Shibata S,. 2005. Glycyrrhetinic acid and related compounds induce G1 arrest and apoptosis in human hepatocellular carcinoma HepG2. Anticancer Res 25: 4043-4047.
35. Shao JJ, Zhang AP, Qin W, et al,. 2012. AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells. Biochem Biophys Res Commun 423: 448-453.
36. Song YH, Jeong SJ, Kwon HY, et al,. 2012. Ursolic acid from Oldenlandia diffusa induces apoptosis via activation of caspases and phosphorylation of glycogen synthase kinase 3 beta in SK-OV-3 ovarian cancer cells. Biol Pharm Bull 35: 1022-1028.
37. Soto-Cerrato V, Vinals F, Lambert JR, et al,. 2007. Prodigiosin induces the proapoptotic gene NAG-1 via glycogen synthase kinase-3beta activity in human breast cancer cells. Mol Cancer Ther 6: 362-369.
38. Sun Z, Liang ST, Zhai XF, et al,. 2012. A traditional Chinese herbal medicine compound preparation versus interventional therapy after resection of small hepatocellular carcinoma: 22-year follow-up. J Tradit Chin Med 32: 156-163.
39. Sutherland C, Leighton IA, Cohen P,. 1993. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J 296 (Pt 1): 15-19.
40. Tan J, Shen ZX, Geng W,. 2006. Ursolic acid induces apoptosis in colon cancer HT-29 cells. Zhonghua Zhong Liu Za Zhi 28: 99-102.
41. Tang C, Lu YH, Xie JH, et al,. 2009. Downregulation of survivin and activation of caspase-3 through the PI3K/Akt pathway in ursolic acid-induced HepG2 cell apoptosis. Anticancer Drugs 20: 249-258.
42. Tsukamoto S, Yokosawa H,. 2010. Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy. Planta Med 76: 1064-1074.
43. Urbanska K, Trojanek J, Del Valle L, et al,. 2007. Inhibition of IGF-I receptor in anchorage-independence attenuates GSK-3beta constitutive phosphorylation and compromises growth and survival of medulloblastoma cell lines. Oncogene 26: 2308-2317.
44. Villanueva A, Llovet JM,. 2012. Second-line therapies in hepatocellular carcinoma: emergence of resistance to sorafenib. Clin Cancer Res 18: 1824-1826.
45. Wang X, Li L, Wang B, et al,. 2009a. Effects of ursolic acid on the proliferation and apoptosis of human ovarian cancer cells. J Huazhong Univ Sci Technolog Med Sci 29: 761-764.
46. Wang Y, Feng W, Xue W, et al,. 2009b. Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 58: 1391-1402.
47. Wang J, Li Y, Wang X, et al,. 2012. Ursolic acid inhibits proliferation and induces apoptosis in human glioblastoma cell lines U251 by suppressing TGF-beta1/miR-21/PDCD4 pathway. Basic Clin Pharmacol Toxicol 111: 106-112.
48. Winder WW,. 2001. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J Appl Physiol 91: 1017-1028.
49. Yan SL, Huang CY, Wu ST, et al,. 2010. Oleanolic acid and ursolic acid induce apoptosis in four human liver cancer cell lines. Toxicol In Vitro 24: 842-848.
50. Yang L, Liu X, Lu Z, et al,. 2010. Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Lett 298: 128-138.
51. Yeh CT, Wu CH, Yen GC,. 2010. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol Nutr Food Res 54: 1285-1295.
52. Yu Y, Lang Q, Chen Z, et al,. 2009. The efficacy for unresectable hepatocellular carcinoma may be improved by transcatheter arterial chemoembolization in combination with a traditional Chinese herbal medicine formula: a retrospective study. Cancer 115: 5132-5138.
53. Zakikhani M, Dowling R, Fantus IG, et al,. 2006. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 66: 10269-10273.
54. Zhang Y, Sreekrishna K, Lin Y, et al,. 2011. Modulation of transient receptor potential (TRP) channels by Chinese herbal extracts. Phytother Res 25: 1666-1670.
55. Zhang P, Cheng Y, Duan RD,. 2012. Ursolic acid inhibits acid sphingomyelinase in intestinal cells. Phytother Res. DOI: 10.1002/ptr.4709.
56. Zheng QY, Jin FS, Yao C, et al,. 2012a. Ursolic acid-induced AMP-activated protein kinase (AMPK) activation contributes to growth inhibition and apoptosis in human bladder cancer T24 cells. Biochem Biophys Res Commun 419: 741-747.
57. Zheng QY, Li PP, Jin FS, et al,. 2012b. Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells. Cell Signal 25: 206-213.