Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
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Asiatic Acid Promotes p21WAF1/CIP1 Protein Stability through Attenuation of NDR1/2 Dependent Phosphorylation of p21WAF1/CIP1 in HepG2 Human Hepatoma Cells

  • Chen, Jin-Yuan (Department of General Surgery, Zhujiang Hospital of Southern Medical University) ;
  • Xu, Qing-Wen (Department of Gastrointestinal Surgery, Affiliated Hospital of Guangdong Medical College) ;
  • Xu, Hong (Department of Pharmacy, Affiliated Hospital of Guangdong Medical College) ;
  • Huang, Zong-Hai (Department of General Surgery, Zhujiang Hospital of Southern Medical University)
  • Published : 2014.01.30
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Abstract

Previous studies have suggested anti-tumor effects of asiatic acid in some human cancer cell lines. This agent is reported to increase the levels of $p21^{WAF1/CIP1}$ in human breast cancer cell lines. However, the molecular mechanisms have not been established. Here we report that asiatic acid up-regulates $p21^{WAF1/CIP1}$ protein expression but not the level of $p21^{WAF1/CIP1}$ mRNA in HepG2 human hepatoma cells. Furthermore, we found that the asiatic acid induced increase of $p21^{WAF1/CIP1}$ protein was associated with decreased phosphorylation (ser-146) of $p21^{WAF1/CIP1}$. Knockdown of NDR1/2 kinase, which directly phosphorylates $p21^{WAF1/CIP1}$ protein at ser-146 and enhances its proteasomal degradation, increased the levels of $p21^{WAF1/CIP1}$ protein and eliminated the regulation of $p21^{WAF1/CIP1}$ stability by asiatic acid. At the same time, the expression of NDR1/2 kinase decreased during treatment with asiatic acid in HepG2 cells. Moreover, asiatic acid inhibited the proliferation of HepG2 cells, this being attenuated by knockdown of $p21^{WAF1/CIP1}$. In conclusion, we propose that asiatic acid inhibits the expression NDR1/2 kinase and promotes the stability of $p21^{WAF1/CIP1}$ protein through attenuating NDR1/2 dependent phosphorylation of $p21^{WAF1/CIP1}$ in HepG2 cells.

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References

  1. Abbas T, Dutta A (2009). p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer, 9, 400-14. https://doi.org/10.1038/nrc2657
  2. Altinbas M, Kalender ME, Oven B, et al (2012). Weekly Topotecan for Recurrent Small Cell Lung Cancer - a Retrospective Anatolian Medical Oncology Group Study. Asian Pac J Cancer Prev, 13, 2909-12. https://doi.org/10.7314/APJCP.2012.13.6.2909
  3. Boreddy SR, Srivastava SK (2013). Pancreatic cancer chemoprevention by phytochemicals. Cancer Lett, 34, 86-94.
  4. Cornils H, Kohler RS, Hergovich A, et al (2011). Human NDR kinases control G(1)/S cell cycle transition by directly regulating p21 stability. Mol Cell Biol, 31, 1382-95. https://doi.org/10.1128/MCB.01216-10
  5. Cragg GM, Newman DJ (2005). Plants as a source of anti-cancer agents. J Ethnopharmacol, 100, 72-79. https://doi.org/10.1016/j.jep.2005.05.011
  6. Grechez-Cassiau A, Rayet B, Guillaumond F, et al (2008). The circadian clock component BMAL1 is a critical regulator of $p21^{WAF1/CIP1}$ expression and hepatocyte proliferation. J Biol Chem, 283, 4535-42. https://doi.org/10.1074/jbc.M705576200
  7. Guo FF, Feng X, Chu ZY, et al (2013). Microbial transformation of asiatic acid. J Asian Nat Prod Res, 15, 15-21. https://doi.org/10.1080/10286020.2012.741124
  8. Gurfinkel DM, Chow S, Hurren R, et al (2006). Disruption of the endoplasmic reticulum and increases in cytoplasmic calcium are early events in cell death induced by the natural triterpenoid Asiatic acid. Apoptosis, 11, 1463-71. https://doi.org/10.1007/s10495-006-9086-z
  9. Harvey AL (2008). Natural products in drug discovery. Drug Discov Today, 13, 894-901. https://doi.org/10.1016/j.drudis.2008.07.004
  10. Hsu YL, Kuo PL, Lin LT, et al (2005). Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogenactivated protein kinase pathways in human breast cancer cells. J Pharmacol Exp Ther, 313, 333-44.
  11. Huang FX, Lin XH, He WN, et al (2012). Two new oxidation products obtained from the biotransformation of asiatic acid by the fungus Fusarium avenaceum AS 3.4594. J Asian Nat Prod Res, 14, 1039-45. https://doi.org/10.1080/10286020.2012.702761
  12. Kan WL, Yin C, Xu HX, et al (2013). Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G(0) /G(1) cell cycle arrest and apoptosis. Int J Cancer, 132, 707-16. https://doi.org/10.1002/ijc.27694
  13. Kavitha CV, Agarwal C, Agarwal R, et al (2011). Asiatic acid inhibits pro-angiogenic effects of VEGF and human gliomas in endothelial cell culture models. PLoS One, 6, e22745. https://doi.org/10.1371/journal.pone.0022745
  14. Lee JY, Yu SJ, Park YG, et al (2007). Glycogen synthase kinase 3beta phosphorylates $p21^{WAF1/CIP1}$ for proteasomal degradation after UV irradiation. Mol Cell Biol, 27, 3187-98. https://doi.org/10.1128/MCB.01461-06
  15. Mondal S, Bandyopadhyay S, Ghosh MK, et al (2012). Natural products: promising resources for cancer drug discovery. Anticancer Agents Med Chem, 12, 49-75. https://doi.org/10.2174/187152012798764697
  16. Nobili S, Lippi D, Witort E, et al (2009). Natural compounds for cancer treatment and prevention. Pharmacol Res, 59, 365-78. https://doi.org/10.1016/j.phrs.2009.01.017
  17. Park BC, Bosire KO, Lee ES, et al (2005). Asiatic acid induces apoptosis in SK-MEL-2 human melanoma cells. Cancer Lett, 218, 81-90. https://doi.org/10.1016/j.canlet.2004.06.039
  18. Phalke S, Mzoughi S, Bezzi M, et al (2012). Voorhoeve PM, Guccione E: p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6. Nucleic Acids Res, 40, 9534-42. https://doi.org/10.1093/nar/gks858
  19. Russo A, Esposito D, Catillo M, et al (2013). Human rpL3 induces G 1/S arrest or apoptosis by modulating p21 (waf1/cip1) levels in a p53-independent manner. Cell Cycle, 12, 76-87. https://doi.org/10.4161/cc.22963
  20. Tang LX, He RH, Yang G, et al (2012). Asiatic acid inhibits liver fibrosis by blocking TGF-beta/Smad signaling in vivo and in vitro. PLoS One, 7, e31350. https://doi.org/10.1371/journal.pone.0031350
  21. Tang XL, Yang XY, Jung HJ, et al (2009). Asiatic acid induces colon cancer cell growth inhibition and apoptosis through mitochondrial death cascade. Biol Pharm Bull, 32, 1399-1405. https://doi.org/10.1248/bpb.32.1399
  22. Xu MF, Xiong YY, Liu JK, et al (2012). Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells. Acta Pharmacol Sin, 33, 578-87. https://doi.org/10.1038/aps.2012.3
  23. Xu W, Zhu Q, Wu Z, et al (2012). A Novel Evolutionarily Conserved Element Is a General Transcriptional Repressor of $p21^{WAF1/CIP1}$. Cancer Res, 72, 6236-46. https://doi.org/10.1158/0008-5472.CAN-12-1236

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