Growth Suppression Effects of Recombinant Adenovirus Expressing Human Lactoferrin on Cervical Cancer In Vitro and In Vivo
Publication: Cancer Biotherapy & Radiopharmaceuticals
Volume 26, Issue Number 4
Abstract
Human lactoferrin (hLF) is a multifunctional glycoprotein that can inhibit cancer growth. The molecular mechanism of hLF-induced tumor growth inhibition is incompletely understood. Moreover, the adenovirus vector-mediated hLF (Ad-hLF) gene therapy on cervical cancer has not been yet characterized. In this study, the replication-deficient Ad-hLF was used to explore tumor growth suppression effects on cervical cancer in vitro and in vivo. The results showed that the recombinant adenovirus encoding hLF delivery resulted in a more differential tumor growth inhibition, and this growth arrest was caused by cell cycle inhibition at G2/M phase. In addition, Fas, a death-inducing receptor, and Bax, a member of pro-apoptotic Bcl-2 family, were increased in the sample of cervical cancer tissue treated by Ad-hLF. Further, it was also observed that caspase-3 was activated and the expression of anti-apoptotic Bcl-2 was decreased. These results indicated that the growth inhibitory effects of Ad-hLF on cervical cancer were caused by elevated expression of Fas and decreased the ratio of anti- to pro-apoptotic molecule Bcl-2/Bax.
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References
1.
Parkin DMBray FFerlay J et al. Global Cancer Statistics, 2002CA Cancer J Clin20055574. 1. Parkin DM, Bray F, Ferlay J, et al. Global Cancer Statistics, 2002. CA Cancer J Clin 2005;55:74.
2.
Lonnerdal BIyer S. Lactoferrin: Molecular structure and biological functionAnnu Rev Nutr19951593. 2. Lonnerdal B, Iyer S. Lactoferrin: Molecular structure and biological function. Annu Rev Nutr 1995;15:93.
3.
Nuijens JBerkel PSchanbacher F. Structure and biological actions of lactoferrinJ Mammary Gland Biol19961285. 3. Nuijens J, Berkel P, Schanbacher F. Structure and biological actions of lactoferrin. J Mammary Gland Biol 1996;1:285.
4.
Levay PViljoen M. Lactoferrin: A general reviewHaematologica199580252. 4. Levay P, Viljoen M. Lactoferrin: A general review. Haematologica 1995;80:252.
5.
Liu TZhang Y-ZWu X-F. High level expression of functionally active human lactoferrin in silkworm larvaeJ Biotechnol2005118246. 5. Liu T, Zhang Y-Z, Wu X-F. High level expression of functionally active human lactoferrin in silkworm larvae. J Biotechnol 2005;118:246.
6.
Vorland LH. Lactoferrin: A multifunctional glycoproteinAPMIS1999107971. 6. Vorland LH. Lactoferrin: A multifunctional glycoprotein. APMIS 1999;107:971.
7.
van der Strate BWABeljaars LMolema G et al. Antiviral activities of lactoferrinAntivir Res200152225. 7. van der Strate BWA, Beljaars L, Molema G, et al. Antiviral activities of lactoferrin. Antivir Res 2001;52:225.
8.
Bezault JBhimani RWiprovnick J et al. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in miceCancer Res1994542310. 8. Bezault J, Bhimani R, Wiprovnick J, et al. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res 1994;54:2310.
9.
Bird RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancerCancer Lett19959355. 9. Bird RP. Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett 1995;93:55.
10.
Magnuson BACarr IBird RP. Ability of aberrant crypt foci characteristics to predict colonic tumor incidence in rats fed cholic acidCancer Res1993534499. 10. Magnuson BA, Carr I, Bird RP. Ability of aberrant crypt foci characteristics to predict colonic tumor incidence in rats fed cholic acid. Cancer Res 1993;53:4499.
11.
Duarte DCNicolau ATeixeira JA et al. The effect of bovine milk lactoferrin on human breast cancer cell linesJ Dairy Sci20119466. 11. Duarte DC, Nicolau A, Teixeira JA, et al. The effect of bovine milk lactoferrin on human breast cancer cell lines. J Dairy Sci 2011;94:66.
12.
Ushida YSekine KKuhara T et al. Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the ratJpn J Cancer Res199990262. 12. Ushida Y, Sekine K, Kuhara T, et al. Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the rat. Jpn J Cancer Res 1999;90:262.
13.
Tanaka TKawabata KKohno H et al. Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 ratsJpn J Cancer Res20009125. 13. Tanaka T, Kawabata K, Kohno H, et al. Chemopreventive effect of bovine lactoferrin on 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Jpn J Cancer Res 2000;91:25.
14.
Fujita K-iOhnishi TSekine K et al. Down-regulation of 2-Amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in ratsCancer Sci200293616. 14. Fujita K-i, Ohnishi T, Sekine K, et al. Down-regulation of 2-Amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx)-induced CYP1A2 expression is associated with bovine lactoferrin inhibition of MeIQx-induced liver and colon carcinogenesis in rats. Cancer Sci 2002;93:616.
15.
Vaux DKorsmeyer S. Cell death in development reviewCell199996245. 15. Vaux D, Korsmeyer S. Cell death in development review. Cell 1999;96:245.
16.
Mader JSSalsman JConrad DM et al. Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell linesMol Cancer Ther20054612. 16. Mader JS, Salsman J, Conrad DM, et al. Bovine lactoferricin selectively induces apoptosis in human leukemia and carcinoma cell lines. Mol Cancer Ther 2005;4:612.
17.
Furlong SJMader JSHoskin DW. Lactoferricin-induced apoptosis in estrogen-nonresponsive MDA-MB-435 breast cancer cells is enhanced by C-6 ceramide or tamoxifenOncol Rep2006151385. 17. Furlong SJ, Mader JS, Hoskin DW. Lactoferricin-induced apoptosis in estrogen-nonresponsive MDA-MB-435 breast cancer cells is enhanced by C-6 ceramide or tamoxifen. Oncol Rep 2006;15:1385.
18.
He TCZhou SBda Costa LT et al. A simplified system for generating recombinant adenovirusesP Natl Acad Sci USA1998952509-2514. 18. He TC, Zhou SB, da Costa LT, et al. A simplified system for generating recombinant adenoviruses. P Natl Acad Sci USA 1998;95:2509–2514.
19.
Ng CJWadleigh DJGangopadhyay A et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoproteinJ Biol Chem200127644444. 19. Ng CJ, Wadleigh DJ, Gangopadhyay A, et al. Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001;276:44444.
20.
Rees SCoote JStables J et al. Bicistronic vector for the creation of stable mammalian cell lines that predisposes all antibiotic-resistant cells to express recombinant proteinBiotechniques199620102-106108. 20. Rees S, Coote J, Stables J, et al. Bicistronic vector for the creation of stable mammalian cell lines that predisposes all antibiotic-resistant cells to express recombinant protein. Biotechniques 1996;20:102, 106, 108.
21.
Hurwitz DRChinnadurai G. Evidence that a second tumor antigen coded by adenovirus early gene region E1a is required for efficient cell transformationProc Natl Acad Sci USA198582163. 21. Hurwitz DR, Chinnadurai G. Evidence that a second tumor antigen coded by adenovirus early gene region E1a is required for efficient cell transformation. Proc Natl Acad Sci USA 1985;82:163.
22.
Zemann NKlein PWetzel E et al. Lactoferrin induces growth arrest and nuclear accumulation of Smad-2 in HeLa cellsBiochimie201092880. 22. Zemann N, Klein P, Wetzel E, et al. Lactoferrin induces growth arrest and nuclear accumulation of Smad-2 in HeLa cells. Biochimie 2010;92:880.
23.
Pardee A. G1 events and regulation of cell proliferationScience1989246603. 23. Pardee A. G1 events and regulation of cell proliferation. Science 1989;246:603.
24.
Weinberg R. The retinoblastoma protein and cell cycle controlCell199581323. 24. Weinberg R. The retinoblastoma protein and cell cycle control. Cell 1995;81:323.
25.
Pines J. Cyclins and cyclin-dependent kinases: A biochemical viewBiochem J1995308Pt 3697. 25. Pines J. Cyclins and cyclin-dependent kinases: A biochemical view. Biochem J 1995;308(Pt 3):697.
26.
Olashaw NPledger WJ. Lactoferrin modifies apoptosis-related gene expression in the colon of the azoxymethane-treated ratSci STKE2002134re7. 26. Olashaw N, Pledger WJ. Lactoferrin modifies apoptosis-related gene expression in the colon of the azoxymethane-treated rat. Sci STKE 2002;(134):re7.
27.
Harbour JWDean DC. Rb function in cell-cycle regulation and apoptosisNat Cell Biol20002E65. 27. Harbour JW, Dean DC. Rb function in cell-cycle regulation and apoptosis. Nat Cell Biol 2000;2:E65.
28.
Koff AGiordano ADesai D et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycleScience19922571689. 28. Koff A, Giordano A, Desai D, et al. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science 1992;257:1689.
29.
Dulic VLees EReed S. Association of human cyclin E with a periodic G1-S phase protein kinaseScience19922571958. 29. Dulic V, Lees E, Reed S. Association of human cyclin E with a periodic G1-S phase protein kinase. Science 1992;257:1958.
30.
Hinds PWMittnacht SDulic V et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclinsCell199270993. 30. Hinds PW, Mittnacht S, Dulic V, et al. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell 1992;70:993.
31.
Hatakeyama MBrill JAFink GR et al. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma proteinGenes Dev199481759. 31. Hatakeyama M, Brill JA, Fink GR, et al. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev 1994;8:1759.
32.
Sell SBecker FFLeffert HL et al. Expression of an oncodevelopmental gene product ({alpha}-Fetoprotein) during fetal development and adult oncogenesisCancer Res19763611_Part_24239. 32. Sell S, Becker FF, Leffert HL, et al. Expression of an oncodevelopmental gene product ({alpha}-Fetoprotein) during fetal development and adult oncogenesis. Cancer Res 1976;36(11_Part_2):4239.
33.
Niwa YMatsumura MShiratori Y et al. Quantitation of alpha-fetoprotein and albumin messenger RNA in human hepatocellular carcinomaHepatology1996231384. 33. Niwa Y, Matsumura M, Shiratori Y, et al. Quantitation of alpha-fetoprotein and albumin messenger RNA in human hepatocellular carcinoma. Hepatology 1996;23:1384.
34.
Saeki TMhashilkar AChada S et al. Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitroGene Ther200072051. 34. Saeki T, Mhashilkar A, Chada S, et al. Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 2000;7:2051.
35.
Noh EJLee J-S. Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2-M transitionBiochem Biophys Res Commun2003310267. 35. Noh EJ, Lee J-S. Functional interplay between modulation of histone deacetylase activity and its regulatory role in G2-M transition. Biochem Biophys Res Commun 2003;310:267.
36.
Cheng Y-LChang W-LLee S-C et al. Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosisLife Sci2004751579. 36. Cheng Y-L, Chang W-L, Lee S-C, et al. Acetone extract of Angelica sinensis inhibits proliferation of human cancer cells via inducing cell cycle arrest and apoptosis. Life Sci 2004;75:1579.
37.
Hu WKavanagh JJ. Anticancer therapy targeting the apoptotic pathwayLancet Oncol20034721. 37. Hu W, Kavanagh JJ. Anticancer therapy targeting the apoptotic pathway. Lancet Oncol 2003;4:721.
38.
Carnero A. Targeting the cell cycle for cancer therapyBr J Cancer200287129. 38. Carnero A. Targeting the cell cycle for cancer therapy. Br J Cancer 2002;87:129.
39.
Fujita K-iMatsuda ESekine K et al. Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated ratsCarcinogenesis2004251961. 39. Fujita K-i, Matsuda E, Sekine K, et al. Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats. Carcinogenesis 2004;25:1961.
40.
Kischkel FCHellbardt SBehrmann I et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptorEMBO J1995145579. 40. Kischkel FC, Hellbardt S, Behrmann I, et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 1995;14:5579.
41.
Boldin MPGoncharov TMGoltsev YV et al. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell deathCell199685803. 41. Boldin MP, Goncharov TM, Goltsev YV, et al. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 1996;85:803.
42.
Muzio MChinnaiyan AMKischkel FC et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death—inducing signaling complexCell199685817. 42. Muzio M, Chinnaiyan AM, Kischkel FC, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death—inducing signaling complex. Cell 1996;85:817.
43.
Lazebnik YAKaufmann SHDesnoyers S et al. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICENature1994371346. 43. Lazebnik YA, Kaufmann SH, Desnoyers S, et al. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 1994;371:346.
44.
Tewari MQuan LTO'Rourke K et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymeraseCell199581801. 44. Tewari M, Quan LT, O'Rourke K, et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995;81:801.
45.
Cheng YLee SLin S et al. Anti-proliferative activity of Bupleurum scrozonerifolium in A549 human lung cancer cells in vitro and in vivoCancer Lett2005222183. 45. Cheng Y, Lee S, Lin S, et al. Anti-proliferative activity of Bupleurum scrozonerifolium in A549 human lung cancer cells in vitro and in vivo. Cancer Lett 2005;222:183.
46.
Nicholson DWThornberry NA. Caspases: Killer proteasesTrends Biochem Sci199722299. 46. Nicholson DW, Thornberry NA. Caspases: Killer proteases. Trends Biochem Sci 1997;22:299.
47.
Salvesen GSDixit VM. Caspases: Intracellular signaling by proteolysisCell199791443. 47. Salvesen GS, Dixit VM. Caspases: Intracellular signaling by proteolysis. Cell 1997;91:443.
48.
Vakkala MLahteenmaki KRaunio H et al. Apoptosis during breast carcinoma progressionClin Cancer Res19995319. 48. Vakkala M, Lahteenmaki K, Raunio H, et al. Apoptosis during breast carcinoma progression. Clin Cancer Res 1999;5:319.
49.
Yang QSakurai TJing X et al. Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinomaPathol Int199949775. 49. Yang Q, Sakurai T, Jing X, et al. Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma. Pathol Int 1999;49:775.
50.
Yang JLiu XBhalla K et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blockedScience19972751129. 50. Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science 1997;275:1129.
Information & Authors
Information
Published In
Cancer Biotherapy & Radiopharmaceuticals
Volume 26 • Issue Number 4 • August 2011
Pages: 477 - 483
PubMed: 21834714
Copyright
Copyright 2011, Mary Ann Liebert, Inc.
History
Published online: 11 August 2011
Published in print: August 2011
Authors
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No competing financial interests exist.
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