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A therapeutic approach to treat prostate cancer by targeting Nm23-H1/h-Prune interaction

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Abstract

Nm23-H1 is a metastasis suppressor gene whose overexpression is associated with both reduced cell motility in various cancers and increased metastatic potential in neuroblastomas, osteosarcomas, and hematological malignances. We previously reported that Nm23-H1 exerts tumor suppressor action in prostate cancer cells and that h-Prune, which is overexpressed in various tumor types, binds Nm23-H1. Moreover, blockage of the Nm23-H1/h-Prune interaction with a competitive permeable peptide (CPP) attenuates migration of breast and neuroblastoma cells. This series of events suggests that the Nm23-H1/h-Prune protein complex regulates cancer progression and that its specific impairment could be a new therapeutic strategy in oncology. We found that CPP leads to inhibition of the AKT/mTORv and NF-kBv signaling pathways and also activates apoptosis. To obtain a proof-of-concept of our hypothesis, we used a xenograft model of prostate cancer to evaluate whether impairment of this complex using CPP results in an anti-tumoral effect. Using a mouse orthotopic model with bioluminescent imaging, we show evidences that CPP reduces prostate cancer metastases formation. In conclusion, CPP being able to impair formation of the h-Prune/Nm23-H1 complex holds promise for the treatment of prostate cancer.

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Acknowledgments

We thank the Service Facilities of CEINGE and Jean Ann Gilder (Scientific Communication srl., Naples, Italy) for editing the text. Financial support for this study was provided by: PRIN (E5AZ5F) 2008 (MZ), Associazione Italiana per la Ricerca sul Cancro (AIRC) 2011–2014 (MZ), FP6-EET pipeline LSH-CT-2006-037260 (MZ), FP7-Tumic HEALTH-F2-2008-201662 (MZ).

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Authors and Affiliations

  1. Centro di Ingegneria Genetica e Biotecnologia Avanzate (CEINGE), Naples, Italy

    Marianeve Carotenuto, Pasqualino de Antonellis, Cristina Maria Chiarolla, Carmela Attanasio, Valentina Damiani, Iolanda Boffa, Nadia Aiese & Massimo Zollo

  2. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli ‘Federico II’, Naples, Italy

    Marianeve Carotenuto, Pasqualino de Antonellis, Cristina Maria Chiarolla, Carmela Attanasio, Valentina Damiani, Iolanda Boffa, Nadia Aiese & Massimo Zollo

  3. Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy

    Emilia Pedone

  4. Haemato-Oncology Laboratory, Department of Paediatrics, University of Padova, Padua, Italy

    Benedetta Accordi & Giuseppe Basso

  5. Dipartimento di Medicina Veterinaria e Produzioni Animali, Università di Napoli ‘Federico II’, Naples, Italy

    Luigi Navas

  6. Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, Università di Napoli ‘Federico II’, Naples, Italy

    Ciro Imbimbo

  7. DAI Dipartimento Assistenziale Medicina Trasfusionale, Azienda Ospedaliera Federico II, Naples, Italy

    Massimo Zollo

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  1. Marianeve Carotenuto
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  2. Pasqualino de Antonellis
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Correspondence to Massimo Zollo.

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This article is published as part of the Special issue on NDPK.

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Supplemental Fig. S1

(a) CPP mRNA expression detected by RT-PCR in DAOY and PC3 cells infected with AdV-MOCK or AdV-CPP. Data are expressed as mRNA expression (2–DCt) values. Data are means ± SD (n = 2) (*P< 0.05; ***P< 0.0005). (b) Representative images of PC3 cells after Adenovirus infection. Upper panels: GFP expression in transduced cells. PC3 cells were infected with Adenovirus Mock at MOI of 100 and visualized by fluorescence microscopy after 24 h. Lower panels: Phase contrast microscopy. (c) Analysis of caspase-3 activity, as measured with a fluorogenic substrate of caspase-3, in PC3 cells 50 hours after infection with AdV-MOCK or AdV-CPP. Caspase 3 activity was unchanged in AdV-CPP-treated PC3 cells compared to AdV-MOCK-infected counterparts. Data are means ±SD derived from triplicate measurements. (GIF 64 kb)

High resolution image (TIFF 400 kb)

Supplemental fig. 2

(a) Intra-prostatic injection of PC3-Luc cells in two NOD/SCID mice groups that were treated with AdV-MOCK (5 mice) or AdV-CPP (5 mice). Tumorigenesis was followed by in-vivo bioluminescence photon emissions signals (IVIS Imaging System). Region of interest (ROI) analysis predominantly quantified light emission from peritumoral tissues. Gray boxes represent the animals that died during the trial. (b-d) Graphs showing lymphocytes, neutrophils (b), platelets (PLT; c) and red blood cells (RBC; d) counts in AdV-MOCK and AdV-CPP-treated mice. Data are means ±SD. (GIF 218 kb)

High resolution image (TIFF 1195 kb)

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Carotenuto, M., de Antonellis, P., Chiarolla, C.M. et al. A therapeutic approach to treat prostate cancer by targeting Nm23-H1/h-Prune interaction. Naunyn-Schmiedeberg's Arch Pharmacol 388, 257–269 (2015). https://doi.org/10.1007/s00210-014-1035-8

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