Fisetin induces G2/M phase cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation in human endometrial cancer cells

  • Zhan-Ying Wang Department of Obstetrics and Gynecology, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China
  • Wen-Qiong Liu Department of Obstetrics and Gynecology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250011, China
  • Si'e Wang Department of Obstetrics and Gynecology, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China
  • Zeng-Tao Wei Department of Obstetrics and Gynecology, Jinan Central Hospital Affiliated to Shandong University, No. 105, Jiefang Road, Lixia District, Jinan, Shandong 250013, China
Keywords: ATM, Chk1/2, Cdc25C, endometrial cancer, fisetin, G2/M cell cycle phase

Abstract

Endometrial cancer is one of the most prevalent gynaecological malignancies where, currently available therapeutic options remain limited. Recently phytochemicals are exploited for their efficiency in cancer therapy. The present study investigates the anti-proliferative effect of fisetin, a flavonoid on human endometrial cancer cells (KLE and Hec1 A). Fisetin (20-100 µM) effectively reduced the viability of Hec1 A and KLE cells and potentially altered the cell population at G2/M stage. Expression levels of the cell cycle proteins (cyclin B1, p-Cdc2, p-Cdc25C, p-Chk1, Chk2, p-ATM, cyclin B1, H2AX, p21 and p27) were analyzed. Fisetin suppressed cyclin B1 expression and caused inactiva-tion of Cdc25C and Cdc2 by increasing their phosphorylation levels and further activated ATM, Chk1 and Chk2. Increased levels of p21 and p27 were observed as well. These results suggest that fisetin induced G2/M cell cycle arrest via inactivating Cdc25c and Cdc2 through activation of ATM, Chk1 and Chk2.

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References

Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001; 15: 2177-96.

Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res. 2004; 24: 2783-840.

Al Rashid ST, Harding SM, Law C, Coackley C, Bristow RG. Proteinprotein interactions occur between p53 phosphoforms and ATM and 53BP1 at sites of exogenous DNA damage. Radiat Res. 2011; 175: 588-98.

Ando T, Kawabe T, Ohara H, Ducommun B, Itoh M, Okamoto T. Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. J Biol Chem. 2001; 276: 42971-77.

Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003; 3: 421-42.

Bulavin DV, Higashimoto Y, Demidenko ZN, Meek S, Graves P, Phillips C, Zhao H, Moody SA, Appella E, Piwnica-Worms H, Fornace AJ Jr. Dual phosphorylation controls Cdc25 phosphatases and mitotic entry. Nat Cell Biol. 2003; 6: 545-51.

Buolamwini JK. Cell cycle molecular targets in novel anticancer drug discovery. Curr Pharm Des. 2000; 6: 379-92.

Chen YC, Shen SC, Lee WR, Lin HY, Ko CH, Shih CM, Yang LL. Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol. 2002; 76: 351-59.

Chou RH, Hsieh SC, Yu YL, Huang MH, Huang YC, Hsieh YH. Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-?B signaling pathway. PLoS ONE 2013; 8: e71983.

Collins K, Jacks T, Pavletich NP. The cell cycle and cancer. Proc Natl Acad Sci USA 1997; 94: 2776-78.

Fernandez-Capetillo O, Mahadevaiah SK, Celeste A, Romanienko PJ, Camerini-Otero RD, Bonner WM, Manova K, Burgoyne P, Nussenzweig A. H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 2003; 4: 497-508.

Garai J, Molnar V, Varga T, Koppan M, Torok A, Bodis J. Endometriosis: harmful survival of an ectopic tissue. Front Biosci. 2006; 11: 595-619.

Haddad AQ, Venkateswaran V, Viswanathan L, Teahan SJ, Fleshner NE, Klotz LH. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 2006; 9: 68-76.

Hajduch M, Havlieek L, Vesely J, Novotny R, Mihal V, Strnad M. Synthetic cyclin dependent kinase inhibitors: New generation of potent anticancer drugs. Adv Exp Med Biol. 1999; 457: 341-53.

Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75: 805-16.

Kastan MB, Lim DS. The many substrates and functions of ATM. Nat Rev Mol Cell Biol. 2000; 1: 179-86.

Kelloff GJ, Crowell JA, Steele VE, Lubet RA, Malone WA, Boone CW, Kopelovich L, Hawk ET, Lieberman R, Lawrence JA, Ali I, Viner JL, Sigman CC. Progress in cancer chemoprevention: Development of diet-derived chemopreventive agents. J Nutr. 2000; 130: 467S-71S.

Khanna KK, Lavin MF, Jackson SP, Mulhern TD. ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 2001; 8: 1052-65.

Kim HJ, Kim SH, Yun JM. Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. Evid Based Complement Alternat Med. 2012; 639-49.

Lee Y, Bae EJ. Inhibition of mitotic clonal expansion mediates fisetin-exerted prevention of adipocyte differentiation in 3T3-L1 cells. Arch Pharm Res. 2013; 36: 1377-84.

Lee WR, Shen SC, Lin HY, Hou WC, Yang LL, Chen YC. Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca2+-dependent endonuclease. Biochem Pharmacol. 2002; 63: 225-36.

Lee HG, Yu KA, Oh WK, Baeg TW, Oh HC, Ahn JS, Jang WC, Kim JW, Lim JS, Choe YK, Yoon DY. Inhibitory effect of jaceosidin isolated from Artemisiaargyi on the function of E6 and E7 oncoproteins of HPV 16. J Ethnopharmacol. 2005; 98: 339-43.

Lee JG, Kim JH, Ahn JH, Lee KT, Baek NI, Choi JH. Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. Food Chem Toxicol. 2013; 55: 214-21.

Leslie KK. Endometrial Cancer. Obstet Gynecol Clin North Am. 2012; 39: 255-68.

Lu X, Jung J, Cho HJ, Lim DY, Lee HS, Chun HS, Kwon DY, Park JH. Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr. 2005b; 135: 2884-90.

Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 1998; 282: 1893-97.

Melchionna R, Chen XB, Blasina A, McGowan CH. Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nat Cell Biol. 2000; 2: 762-65.

Park I, Park KK, Park JH, Chung WY. Isoliquiritigenin induces G2 and M phase arrest by inducing DNA damage and by inhibiting the metaphase/ anaphase transition. Cancer Lett. 2009; 277: 174-81.

Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, Bonner W. Histone H2A variants H2AX and H2AZ. Curr Opin Genet Dev. 2002; 12: 162-69.

Shiloh Y. ATM and related protein kinases: Safe guarding genome integrity. Nat Rev Cancer 2003; 3: 155-68.

Shin SY, Hyun J, Yu JR, Lim Y, Lee YH. 5-Methoxyflavanone induces cell cycle arrest at the G2/M phase, apoptosis and autophagy in HCT116 human colon cancer cells. Toxicol Appl Pharmacol. 2011; 254: 288-98.

Tyagi A, Singh RP, Agarwal C, Siriwardana S, Sclafani RA, Agarwal R. Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells. Carcinogenesis 2005; 26: 1978-87.

Waladkhani AR, Clemens MR. Effect of dietary phytochemicals on cancer development. Int J Mol Med. 1998; 1: 747-53.

Zhou BB, Elledge SJ. The DNA damage response: Putting checkpoints in perspective. Nature 2000; 408: 433-39.

Published
2015-04-03
How to Cite
Wang, Z.-Y., W.-Q. Liu, S. Wang, and Z.-T. Wei. “Fisetin Induces G2/M Phase Cell Cycle Arrest by Inactivating Cdc25C-Cdc2 via ATM-Chk1/2 Activation in Human Endometrial Cancer Cells”. Bangladesh Journal of Pharmacology, Vol. 10, no. 2, Apr. 2015, pp. 279-87, doi:10.3329/bjp.v10i2.21945.
Section
Research Articles