Association de la Recherche contre les Tumeurs de la Prostate ARTP 2014, 19 November, Paris
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1 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILL OMAVIRUS (HPV) L1 WITH NUCLEOPHOSMIN (NPM1), A CONTROLLER OF ANDROGEN RECEPTOR TRANSCRIPTION Association de la Recherche contre les Tumeurs de la Prostate ARTP 2014, 19 November, Paris Background: We showed previously that HPV contained Prostatic Cancer (PC) related oncogenic proteins: 1 ) HPV E2 (51-112) is homologous to an Epidermal Growth Factor (Tran MKG, 1997) 2 ) E1 to PTEN, E6 and L1 to the c-myc inhibitor Bin-1 (Bridging integrator 1 or amphiphysin II), a tumor suppressor deleted in 42% of PC (Tran GMK, 2008) 3 ) HPV-18 E2 mimics Osteoprotegerin and ParaTHormone related Protein (PTHrP) active site (explaining bone metastasis) Anwar K (1992) found 80% HPV-18 in metastatic PC in 1 / 6
2 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS ( Japan Our meta-analysis concluded to a frequency of about 30%-40% (21-80%) oncogenic HPV (-16, -18, -33) in PC (EuroConf Cancer Pasteur Inst, 2004) The most important point is the PCR (E6 primer and fresh tissue ); L1 primer and formalin-fixed, paraffin-embedded yielded negative results For example, Terris MK (1997) obtained 21% positivity with E6 and 0% with L1 primer, in the same patients Recent results confirm that use of paraffin-embedded tissues (Groom HCT, 2012; Ghasemian E, 2013) or L1 primer (Sylvestre RV, 2009) or both (13/104 versus 8/104 Aghakhani A, 2011) were unsuccessful Positive results were reported (in 105% Jalilvand S, 2014; worse overal survival, Pascale M, 2013) Noda S (1975) described papillomavirus-like particles in electron microscopy of prostate cancer tissue Whitaker NJ (2013) found koilocytes in HPV-18 infected prostate cancer Our aim is to link HPV to Androgen Receptor (AR) Another hormonal cancer linked to virus is breast cancer, as the virus integration site is Aromatase, the estrogen synthetizing enzyme (Tekmal RR, 1995) Methods: Amino Acid (AA) sequence comparison between HPV (Lowe J, 2008) and NPM1 (nucleophosmin), which controls AR transcriptional activity by promoting S-phase entry and hyperproliferation (cyclin switch D1 to E1 and p27kip1 loss) (Boudra R, ARTP 2013) Clinically, high p27kip1 is a correlate of better survival after prostatectomy at 5 years 2 / 6
3 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS ( Results: HPV L1 chimera (types 16, 18, 31, 33, 44, 56, 66, 115) [type-16, AA ] is homologous to NPM1 chimera (human, duck, alligator, sheep, rhinoceros, turtle, )[AA 1-48] NPM1 MEDSMDMDSMQPLRPQMFLFGC- - - SGAHWARISPCSLLGGFFAGCELKSD HPV L1 VEDSMDV SMDPKQIQMFLI GCKPPTGEHWAR-SPCSPVG- --AGDCELKSD Conclusion: Anti-androgen escape may be explained by AR mutations, but also in a PC subset (about perhaps 30%-40%, depending on the number of HPV serotypes screened) by a viral infection (oncogenic HPV), as HPV L1 is a viral NPM1 mimetic, enhancing AR transcriptional activity and inducing lethal p27kip1 loss Japanese mushroom Shii take is a non toxic and highly efficient anti-hpv (Smith JA, 2014) Indole 3 carbinol from cruciferous vegetables (Brussels sprouts, broccoli) are efficient against HPV-16 by viral transcription inhibition (Bradlow HL, 1999; Rieck GC, 2006) Anti-cancer drugs discovered by HPV-18 infected KB cells screening (Perdue RE Jr, 1982) may act, by serenpidity, as anti-hpv : Taxol (Paclitaxel, Docetaxel, Cabazitaxel), topotecan, Vinca Alkaloids (Vinorelbine, Vinflunine) HPV vaccination 3 / 6
4 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS ( of young men could protect against PC Bibliography Aghakhani A Scand J Infect Dis 2011, 43: 64-9Anwar K et al Presence of ras oncogene mutations and human papillomavirus DNA in human prostate carcinomas Cancer Res 1992, 52: Boudra R et al Nucleophosmin overexpression down-regulates p27kip1 and induces hyperproliferation in the prostate gland of transgenic mice ARTP 2013 Bradlow HL Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent Ann N Y Acad Sci 1999, 889: Review De Villiers EM Breast Cancer Res 2005, 7: R1-R11 Ghasemian E Asian Pacific J Cancer Prev 14: Groom HCT PLoS ONE 2012, 7(3): e34221 Jalilvand S Asian Pac J Cancer Prev 15 (17), Lowe J et al Evolutionary and structural analyses of alpha-papillomavirus capsid proteins yields novel insights into L2 structure and interaction with L1 Virol J 2008, 5: 150 Noda S The Kurume Med J 1975, 22: Pascale M Disease Markers 2013, 35: Perdue RE Jr KB cell culture I Role in discovery of antitumor agents from higher plants J Nat Prod 1982, 45: / 6
5 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS ( Rieck GC Mol Nutr Food Res 2006, 52: Smith JA et al Evaluation of active hexose correlated compound (AHCC) for the eradication of HPV infections in women with HPV positive Pap smears Int Conf Soc Integrative Oncology, Houston, Oct 28, 2014 Tekmal RR, Durgam VR The overexpression of int-5/aromatase, a novel MMTV integration locus gene, is responsible for D2 mammary tumor cell proliferation Cancer Lett 1995, 88: Terris MK Urology 1997, 50: Tran GMK et al Role of human papillomavirus type 18 in a subgroup of prostatic cancer with bone metastases: Its protein E2 contains the osteoprotegerin active site EuroConf Cancer, Pasteur Institute, Jan , Paris (Free on: Positifsorg C53) Tran MKG et al Human papillomavirus (HPV) E2 protein contains a chimera of epidermal growth factor (EGF) and EGF family mitogens: Heregulin and tumor growth factor 6th Europ Conf Clin Aspects Treatment HIV infection, Hamburg, Germany, Oct 11-15,1997: P474 Tran GMK et al Cancer de la prostate métastatique: Le suppresseur de tumeur Bin1, inhibiteur de c-myc, est homologue aux protéines E6 et L1 des papillomavirus humains oncogènes et PTEN à la protéine E1 Bull Cancer 2008, 95: 592 P33 Whitaker NJ Prostate 2013, 73: / 6
6 C95- PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS ( 6 / 6
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