PROSTATIC CANCER OF VIRAL ORIGIN: HOMOLOGY OF HUMAN ONCOGENIC PAPILLOMAVIRUS (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 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 10.5% 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.

 

Results: HPV L1 chimera (types 16, 18, 31, 33, 44, 56, 66, 115) [type-16, AA 167-219] 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 Shiitake 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 of young men could protect against PC.

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