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Open Access 01-12-2011 | Research

Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways

Authors: Ayesha Rashid, Caiqiong Liu, Toran Sanli, Evangelia Tsiani, Gurmit Singh, Robert G Bristow, Ian Dayes, Himu Lukka, James Wright, Theodoros Tsakiridis

Published in: Radiation Oncology | Issue 1/2011

Abstract

Background

Prostate cancer (PrCa) displays resistance to radiotherapy (RT) and requires radiotherapy dose escalation which is associated with greater toxicity. This highlights a need to develop radiation sensitizers to improve the efficacy of RT in PrCa. Ionizing radiation (IR) stimulates pathways of IR-resistance and survival mediated by the protein kinase Akt but it also activates the metabolic energy sensor and tumor suppressor AMP-Activated Protein Kinase (AMPK). Here, we examined the effects of the polyphenol resveratrol (RSV) on the IR-induced inhibition of cell survival, modulation of cell cycle and molecular responses in PrCa cells.

Methods

Androgen-insensitive (PC3), sensitive (22RV1) PrCa and PNT1A normal prostate epithelial cells were treated with RSV alone (2.5-10 μM) or in combination with IR (2-8 Gy). Clonogenic assays, cell cycle analysis, microscopy and immunoblotting were performed to assess survival, cell cycle progression and molecular responses.

Results

RSV (2.5-5 μM) inhibited clonogenic survival of PC3 and 22RV1 cells but not of normal prostate PNT1A cells. RSV specifically sensitized PrCa cells to IR, induced cell cycle arrest at G1-S phase and enhanced IR-induced nuclear aberrations and apoptosis. RSV enhanced IR-induced expression of DNA damage (γH2Ax) and apoptosis (cleaved-caspase 3) markers as well as of the cell cycle regulators p53, p21^cip1 and p27^kip1. RSV enhanced IR-activation of ATM and AMPK but inhibited basal and IR-induced phosphorylation of Akt.

Conclusions

Our results suggest that RSV arrests cell cycle, promotes apoptosis and sensitizes PrCa cells to IR likely through a desirable dual action to activate the ATM-AMPK-p53-p21^cip1/p27^kip1 and inhibit the Akt signalling pathways.

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Zietman AL, Bae K, Slater JD, Shipley WU, Efstathiou JA, Coen JJ, Bush DA, Lunt M, Spiegel DY, Skowronski R, Jabola BR, Rossi CJ: Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/american college of radiology 95-09. J Clin Oncol 2010,28(7):1106-1111. 10.1200/JCO.2009.25.8475PubMedCentralCrossRefPubMed

Cantley LC: The phosphoinositide 3-kinase pathway. Science 2002,296(5573):1655-1657. 10.1126/science.296.5573.1655CrossRefPubMed

Rodemann HP, Dittmann K, Toulany M: Radiation-induced EGFR-signaling and control of DNA-damage repair. Int J Radiat Biol 2007,83(11-12):781-791. 10.1080/09553000701769970CrossRefPubMed

Burgering BM, Coffer PJ: Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction [see comments]. Nature 1995,376(6541):599-602. 10.1038/376599a0CrossRefPubMed

Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997,7(4):261-269. 10.1016/S0960-9822(06)00122-9CrossRefPubMed

Viniegra JG, Martinez N, Modirassari P, Losa JH, Parada Cobo C, Lobo VJ, Luquero CI, Alvarez-Vallina L, Ramon y, Cajal S, Rojas JM, Sanchez-Prieto R: Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM. J Biol Chem 2005,280(6):4029-4036.CrossRefPubMed

Nelson EC, Evans CP, Mack PC, Devere-White RW, Lara PN Jr: Inhibition of Akt pathways in the treatment of prostate cancer. Prostate Cancer Prostatic Dis 2007,10(4):331-339. 10.1038/sj.pcan.4500974CrossRefPubMed

Mayo LD, Donner DB: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001,98(20):11598-11603. 10.1073/pnas.181181198PubMedCentralCrossRefPubMed

Li Y, Dowbenko D, Lasky LA: AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 2002,277(13):11352-11361. 10.1074/jbc.M109062200CrossRefPubMed

10.

Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M: Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 2002,8(10):1136-1144. 10.1038/nm762CrossRefPubMed

11.

Contessa JN, Hampton J, Lammering G, Mikkelsen RB, Dent P, Valerie K, Schmidt-Ullrich RK: Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. Oncogene 2002,21(25):4032-4041. 10.1038/sj.onc.1205500CrossRefPubMed

12.

Diaz R, Nguewa PA, Diaz-Gonzalez JA, Hamel E, Gonzalez-Moreno O, Catena R, Serrano D, Redrado M, Sherris D, Calvo A: The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer 2009,100(6):932-940. 10.1038/sj.bjc.6604938PubMedCentralCrossRefPubMed

13.

Steinberg GR, Kemp BE: AMPK in Health and Disease. Physiol Rev 2009,89(3):1025-1078. 10.1152/physrev.00011.2008CrossRefPubMed

14.

Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB: AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005,18(3):283-293. 10.1016/j.molcel.2005.03.027CrossRefPubMed

15.

Sanli T, Rashid A, Liu C, Harding S, Bristow RG, Cutz JC, Singh G, Wright J, Tsakiridis T: Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells. Int J Radiat Oncol Biol Phys 2010,78(1):221-229. 10.1016/j.ijrobp.2010.03.005CrossRefPubMed

16.

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(5A):2783-2840.PubMed

17.

Carbo N, Costelli P, Baccino FM, Lopez-Soriano FJ, Argiles JM: Resveratrol, a natural product present in wine, decreases tumour growth in a rat tumour model. Biochem Biophys Res Commun 1999,254(3):739-743. 10.1006/bbrc.1998.9916CrossRefPubMed

18.

Scarlatti F, Sala G, Ricci C, Maioli C, Milani F, Minella M, Botturi M, Ghidoni R: Resveratrol sensitization of DU145 prostate cancer cells to ionizing radiation is associated to ceramide increase. Cancer Lett 2007,253(1):124-130. 10.1016/j.canlet.2007.01.014CrossRefPubMed

19.

Zoberi I, Bradbury CM, Curry HA, Bisht KS, Goswami PC, Roti Roti JL, Gius D: Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines. Cancer Lett 2002,175(2):165-173. 10.1016/S0304-3835(01)00719-4CrossRefPubMed

20.

Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, Kim MK, Viollet B, Chung JH: AMPK-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes 2009.

21.

Kimura Y, Okuda H: Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice. J Nutr 2001,131(6):1844-1849.PubMed

22.

Aziz MH, Nihal M, Fu VX, Jarrard DF, Ahmad N: Resveratrol-caused apoptosis of human prostate carcinoma LNCaP cells is mediated via modulation of phosphatidylinositol 3'-kinase/Akt pathway and Bcl-2 family proteins. Mol Cancer Ther 2006,5(5):1335-1341. 10.1158/1535-7163.MCT-05-0526CrossRefPubMed

23.

Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA: Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 2006,55(8):2180-2191. 10.2337/db05-1188CrossRefPubMed

24.

Hwang J-T, et al.: Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathways. Ann NY Acad Sci 2007,1095(1):441-448. 10.1196/annals.1397.047CrossRefPubMed

25.

Sexton E, Van Themsche C, LeBlanc K, Parent S, Lemoine P, Asselin E: Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer 2006, 5: 45. 10.1186/1476-4598-5-45PubMedCentralCrossRefPubMed

26.

Sabolic I, Brown D: Water channels in renal and nonrenal tissues. NIPS 1995, 10: 12-17.

27.

Bromfield GP, Meng A, Warde P, Bristow RG: Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill. Prostate Cancer Prostatic Dis 2003,6(1):73-85. 10.1038/sj.pcan.4500628CrossRefPubMed

28.

Sramkoski RM, Pretlow TG, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D, Jacobberger JW: A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim 1999,35(7):403-409. 10.1007/s11626-999-0115-4CrossRefPubMed

29.

Bussink J, van der Kogel AJ, Kaanders JH: Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 2008,9(3):288-296. 10.1016/S1470-2045(08)70073-1CrossRefPubMed

30.

Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC: Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 2004,64(24):9152-9159. 10.1158/0008-5472.CAN-04-2727CrossRefPubMed

31.

Gescher AJ, Steward WP: Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomarkers Prev 2003,12(10):953-957.PubMed

32.

Shankar S, Singh G, Srivastava RK: Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. Front Biosci 2007, 12: 4839-4854. 10.2741/2432CrossRefPubMed

33.

Skvortsova I, Skvortsov S, Stasyk T, Raju U, Popper BA, Schiestl B, von Guggenberg E, Neher A, Bonn GK, Huber LA, Lukas P: Intracellular signaling pathways regulating radioresistance of human prostate carcinoma cells. Proteomics 2008,8(21):4521-4533. 10.1002/pmic.200800113CrossRefPubMed

34.

Li L, Ross AH: Why is PTEN an important tumor suppressor? J Cell Biochem 2007,102(6):1368-1374. 10.1002/jcb.21593CrossRefPubMed

35.

Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, Vessella RL, Neubauer BL: Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 2000,275(32):24500-24505. 10.1074/jbc.M003145200CrossRefPubMed

36.

Hsieh TC, Wu JM: Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res 1999,249(1):109-115. 10.1006/excr.1999.4471CrossRefPubMed

37.

Rusin M, Zajkowicz A, Butkiewicz D: Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1. Mech Ageing Dev 2009,130(8):528-537. 10.1016/j.mad.2009.06.005CrossRefPubMed

38.

Ahmad N, Adhami VM, Afaq F, Feyes DK, Mukhtar H: Resveratrol causes WAF-1/p21-mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin Cancer Res 2001,7(5):1466-1473.PubMed

39.

Gill C, Walsh SE, Morrissey C, Fitzpatrick JM, Watson RW: Resveratrol sensitizes androgen independent prostate cancer cells to death-receptor mediated apoptosis through multiple mechanisms. Prostate 2007,67(15):1641-1653. 10.1002/pros.20653CrossRefPubMed

40.

Shih A, Zhang S, Cao HJ, Boswell S, Wu YH, Tang HY, Lennartz MR, Davis FB, Davis PJ, Lin HY: Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. Mol Cancer Ther 2004,3(11):1355-1364.PubMed

41.

Castedo M, Perfettini JL, Roumier T, Andreau K, Medema R, Kroemer G: Cell death by mitotic catastrophe: a molecular definition. Oncogene 2004,23(16):2825-2837. 10.1038/sj.onc.1207528CrossRefPubMed

42.

Gurumurthy S, Vasudevan KM, Rangnekar VM: Regulation of apoptosis in prostate cancer. Cancer Metastasis Rev 2001,20(3-4):225-243.CrossRefPubMed

43.

Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB: The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007,9(2):218-224. 10.1038/ncb1537CrossRefPubMed

Title: Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways
Authors: Ayesha Rashid
Caiqiong Liu
Toran Sanli
Evangelia Tsiani
Gurmit Singh
Robert G Bristow
Ian Dayes
Himu Lukka
James Wright
Theodoros Tsakiridis
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Radiation Oncology / Issue 1/2011
Electronic ISSN: 1748-717X
DOI: https://doi.org/10.1186/1748-717X-6-144

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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