Alpinetin suppresses proliferation of human hepatoma cells by the activation of MKK7 and elevates sensitization to cis-diammined dichloridoplatium Retraction in /10.3892/or.2023.8534

Tang,Bo; Du,Jian; Wang,Jingwen; Tan,Guang; Gao,Zhenming; Wang,Zhongyu; Wang,Liming

doi:10.3892/or.2011.1580

Alpinetin suppresses proliferation of human hepatoma cells by the activation of MKK7 and elevates sensitization to cis-diammined dichloridoplatium

Retraction in: /10.3892/or.2023.8534

Authors:
- Bo Tang
- Jian Du
- Jingwen Wang
- Guang Tan
- Zhenming Gao
- Zhongyu Wang
- Liming Wang
View Affiliations

Affiliations: Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116027, P.R. China, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116011, P.R. China, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian 116027, P.R. China
Published online on: December 6, 2011 https://doi.org/10.3892/or.2011.1580
Pages: 1090-1096

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Alpinetin is a type of novel plant flavonoid derived from Alpinia katsumadai Hayata, found to possess strong anti-hepatoma effects. However, the detailed antitumor mechanism of Alpinetin remains unclear. Mitogen-activated protein kinase kinase-7 (MKK7) can regulate cellular growth, differentiation and apoptosis. The aim of this study was to investigate the role of MKK7 in the anti-hepatoma effect mediated by Alpinetin. HepG2 cells were treated with Alpinetin at various doses and for different times, and the levels of phosphorylated MKK7 (p-MKK7) and total MKK7 were tested by RT-PCR and western blotting. Following transient transfection with RNA interference, cell viability and cell cycle stage were determined using methyl thiazolyl tetrazolium assay and flow cytometry, in order to assess the antitumor action of Alpinetin. In addition, chemosensitization to cis-diammined dichloridoplatium (CDDP) by Alpinetin was assessed by cell counting array and the cell growth inhibitory rate was calculated. The results showed that Alpinetin suppressed HepG2 cell proliferation and arrested cells in the G0/G1 phase by up-regulating the expression levels of p-MKK7. On the contrary, inhibiting the expression of MKK7 reversed the antitumor effect of Alpinetin. Moreover, Alpinetin enhanced the sensitivity of HepG2 hepatoma cells to the chemotherapeutic agent CDDP. Taken together, our studies indicate that activation of MKK7 mediates the anti-hepatoma effect of Alpinetin. MKK7 may be a putative target for molecular therapy against hepatoma and Alpinetin could serve as a potential agent for the development of hepatoma therapy.

View Figures

View References

1	Rampone B, Schiavone B, Martino A, Viviano C and Confuorto G: Current management strategy of hepatocellular carcinoma. World J Gastroenterol. 15:3210–3216. 2009. View Article : Google Scholar : PubMed/NCBI
2	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
3	Rahbari NN, Mehrabi A, Mollberg NM, Müller SA, Koch M, Büchler MW and Weitz J: Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg. 253:453–469. 2011. View Article : Google Scholar : PubMed/NCBI
4	Merle P and Mornex F: Medical therapies for hepatocellular carcinoma. Cancer Radiother. 15:28–31. 2011.
5	Llovet JM, Fuster J and Bruix J: The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 10:S115–S120. 2004. View Article : Google Scholar : PubMed/NCBI
6	Vogel S, Ohmayer S, Brunner G and Heilmann J: Natural and non-natural prenylated chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg Med Chem. 16:4286–4293. 2008. View Article : Google Scholar : PubMed/NCBI
7	Tang J, Li N, Dai H and Wang K: Chemical constituents from seeds of Alpinia katsumadai, inhibition on NF-kappaB activation and anti-tumor effect. Zhongguo Zhong Yao Za Zhi. 35:1710–1714. 2010.PubMed/NCBI
8	He W, Li Y, Tang J, Luan F, Jin J and Hu Z: Comparison of the characterization on binding of alpinetin and cardamonin to lysozyme by spectroscopic methods. Int J Biol Macromol. 39:165–173. 2006. View Article : Google Scholar : PubMed/NCBI
9	Wang S, Zhou L, He W and Hu Z: Separation and determination of alpinetin and cardamonin by reverse micelle electrokinetic capillary chromatography. J Pharm Biomed Anal. 43:1557–1561. 2007. View Article : Google Scholar : PubMed/NCBI
10	Malek SN, Phang CW, Ibrahim H, Norhanom AW and Sim KS: Phytochemical and cytotoxic investigations of Alpinia mutica rhizomes. Molecules. 16:583–589. 2011. View Article : Google Scholar : PubMed/NCBI
11	In LL, Azmi MN, Ibrahim H, Awang K and Nagoor NH: 1′S-1′-acetoxyeugenol acetate: a novel phenylpropanoid from Alpinia conchigera enhances the apoptotic effects of paclitaxel in MCF-7 cells through NF-κB inactivation. Anticancer Drugs. 22:424–434. 2011.
12	He ZH, Ge W, Yue GG, Lau CB, He MF and But PP: Anti-angiogenic effects of the fruit of Alpinia oxyphylla. J Ethnopharmacol. 132:443–449. 2010. View Article : Google Scholar : PubMed/NCBI
13	Suzuki A, Guicheux J, Palmer G, Miura Y, Oiso Y, Bonjour JP and Caverzasio J: Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation. Bone. 30:91–98. 2002. View Article : Google Scholar : PubMed/NCBI
14	Molton SA, Todd DE and Cook SJ: Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3′-kinase (PI3K) pathway is inhibited. Oncogene. 22:4690–4701. 2003.
15	Chang L and Karin M: Mammalian MAP kinase signalling cascades. Nature. 410:37–40. 2001. View Article : Google Scholar : PubMed/NCBI
16	Dérijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ and Davis RJ: Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 267:682–685. 1995.
17	Kishimoto H, Nakagawa K, Watanabe T, Kitagawa D, Momose H, Seo J, Nishitai G, Shimizu N, Ohata S, Tanemura S, Asaka S, Goto T, Fukushi H, Yoshida H, Suzuki A, Sasaki T, Wada T, Penninger JM, Nishina H and Katada T: Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. J Biol Chem. 278:16595–16601. 2003. View Article : Google Scholar : PubMed/NCBI
18	Tournier C, Dong C, Turner TK, Jones SN, Flavell RA and Davis RJ: MKK7is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 15:1419–1426. 2001. View Article : Google Scholar : PubMed/NCBI
19	Finch A, Holland P, Cooper J, Saklatvala J and Kracht M: Selective activation of JNK/SAPK by interleukin-1 in rabbit liver is mediated by MKK7. FEBS Lett. 418:144–148. 1997. View Article : Google Scholar : PubMed/NCBI
20	Wang X, Destrument A and Tournier C: Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta. 1773:1349–1357. 2007. View Article : Google Scholar : PubMed/NCBI
21	Choi JE, Hur W, Jung CK, Piao LS, Lyoo K, Hong SW, Kim SW, Yoon HY and Yoon SK: Silencing of 14-3-3ζ over-expression in hepatocellular carcinoma inhibits tumor growth and enhances chemosensitivity to cis-diammined dichloridoplatium. Cancer Lett. 303:99–107. 2011.
22	Raman M, Chen W and Cobb MH: Differential regulation and properties of MAPKs. Oncogene. 26:3100–3112. 2007. View Article : Google Scholar : PubMed/NCBI
23	Saito H: Regulation of cross-talk in yeast MAPK signaling pathways. Curr Opin Microbiol. 13:677–683. 2010. View Article : Google Scholar : PubMed/NCBI
24	Galeotti N and Ghelardini C: Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation. Int J Neuropsychopharmacol. 20:1–13. 2011.PubMed/NCBI
25	Huang P, Han J and Hui L: MAPK signaling in inflammation-associated cancer development. Protein Cell. 1:218–226. 2010. View Article : Google Scholar : PubMed/NCBI
26	Bermudez O, Pagès G and Gimond C: The dual-specificity MAP kinase phosphatases: critical roles in development and cancer. Am J Physiol Cell Physiol. 299:C189–C202. 2010. View Article : Google Scholar : PubMed/NCBI
27	Haeusgen W, Herdegen T and Waetzig V: The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. Eur J Cell Biol. 90:536–544. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hammaker DR, Boyle DL, Inoue T and Firestein GS: Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 9:R572007. View Article : Google Scholar : PubMed/NCBI
29	Tu Z, Mooney SM and Lee FS: A subdomain of MEKK1 that is critical for binding to MKK4. Cell Signal. 15:65–77. 2003. View Article : Google Scholar : PubMed/NCBI
30	Zhang Q, Tian H, Fu X and Zhang G: Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats. Life Sci. 74:37–45. 2003. View Article : Google Scholar : PubMed/NCBI
31	Takekawa M, Tatebayashi K and Saito H: Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Mol Cell. 18:295–306. 2005. View Article : Google Scholar : PubMed/NCBI
32	Mooney LM and Whitmarsh AJ: Docking interactions in the c-Jun N-terminal kinase pathway. J Biol Chem. 279:11843–11852. 2003. View Article : Google Scholar : PubMed/NCBI
33	Mondal S and Mandal C, Sangwan R, Chandra S and Mandal C: Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Mol Cancer. 9:2392010.
34	Yang MD, Lai KC, Lai TY, Hsu SC, Kuo CL, Yu CS, Lin ML, Yang JS, Kuo HM, Wu SH and Chung JG: Phenethyl isothiocyanate inhibits migration and invasion of human gastric cancer AGS cells through suppressing MAPK and NF-kappaB signal pathways. Anticancer Res. 30:2135–2143. 2010.PubMed/NCBI
35	Dai Y, Guzman ML, Chen S, Wang L, Yeung SK, Pei XY, Dent P, Jordan CT and Grant S: The NF (Nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol. 151:70–83. 2010.
36	Terada Y, Nakashima O, Inoshita S, Kuwahara M, Sasaki S and Marumo F: Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. Nephrol Dial Transplant. 1:45–47. 1999. View Article : Google Scholar : PubMed/NCBI
37	Taylor JL, Szmulewitz RZ, Lotan T, Hickson J, Griend DV, Yamada SD, Macleod K and Rinker-Schaeffer CW: New paradigms for the function of JNKK1/MKK4 in controlling growth of disseminated cancer cells. Cancer Lett. 272:12–22. 2008. View Article : Google Scholar : PubMed/NCBI