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

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.

Janus-faces of NME–oncoprotein interactions

“…Most importantly, the authors identified an inhibitor of Prune that also inhibited Prune-mediated increases in cell motility, thus demonstrating as proof of principle the notion of Prune as a target for anti-metastatic therapy. This idea has subsequently been developed in a most interesting direction to investigate the principal of targeting the NME-PRUNE interaction as a potential therapeutic avenue (Carotenuto et al 2014a).…”

Oncogenic Epstein–Barr virus recruits Nm23-H1 to regulate chromatin modifiers

“…101 In mouse xenograft models, a loss of metastatic activity was observed. 101 Therefore, this has potential for therapeutic intervention as hPrune induction was observed in several cancer types, such as breast, esophageal squamous cell and gastric cancers.…”

“…101 In mouse xenograft models, a loss of metastatic activity was observed. 101 Therefore, this has potential for therapeutic intervention as hPrune induction was observed in several cancer types, such as breast, esophageal squamous cell and gastric cancers. 38,102,103 Further, a downstream target of Nm23-H1, lysophosphatidic acid receptor 1 (LPA1) if inhibited can have therapeutic implications as the expression of LPA1 was suppressed by Nm23-H1 induction with antimetastatic effects.…”

The NDPK/NME superfamily: state of the art

“…98 Taken together, these data strongly suggest that re-expression of NME1 in invasive cancer cells could constitute a promising strategy for anti-metastatic therapy. 99,100 NME IN MEMBRANE REMODELING AND NUCLEOTIDE CHANNELING Studies using several model systems, including Drosophila melanogaster, Caenorhabditis elegans, and mouse, as well as human, have demonstrated a fundamental role of the NME/NDPK family in endocytosis, intracellular trafficking, and nucleotide channeling (Figure 1). The starting point was a report in 2001 by neurobiologists, demonstrating a genetic and functional interaction between Awd and Shibire, the NME/NDPK and dynamin homologs, respectively, in D. melanogaster.…”