PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases

Abstract

We describe here the molecular basis of the complex formation of PRUNE1 with the tumor metastasis suppressors NME1 and NME2, two isoforms appertaining to the nucleoside diphosphate kinase (NDPK) enzyme family, and how this complex regulates signaling the immune system and energy metabolism, thereby shaping the tumor microenvironment (TME). Disrupting the interaction between NME1/2 and PRUNE1, as suggested, holds the potential to be an excellent therapeutic target for the treatment of cancer and the inhibition of metastasis dissemination. Furthermore, we postulate an interaction and regulation of the other Class I NME proteins, NME3 and NME4 proteins, with PRUNE1 and discuss potential functions. Class I NME1–4 proteins are NTP/NDP transphosphorylases required for balancing the intracellular pools of nucleotide diphosphates and triphosphates. They regulate different cellular functions by interacting with a large variety of other proteins, and in cancer and metastasis processes, they can exert pro- and anti-oncogenic properties depending on the cellular context. In this review, we therefore additionally discuss general aspects of class1 NME and PRUNE1 molecular structures as well as their posttranslational modifications and subcellular localization. The current knowledge on the contributions of PRUNE1 as well as NME proteins to signaling cascades is summarized with a special regard to cancer and metastasis.

Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules

“…This molecule was also found able to decrease Prune-1 mRNA and protein levels in different Gr3 MB [15] and triple-negative breast cancer (TNBC) [28] cells. In vitro and in vivo assays also showed the ability of AA7.1 to decrease the cell proliferative and migratory processes, impairing PRUNE-1-and NME1-related signaling and influencing cancer energy metabolism, the TME, and metastasis [25]. In detail, in Gr3 MB, AA7.1 impaired the metastatic axis driven by Prune-1, thus leading to impairment in TGF-β, decreased levels of OTX2, the up-regulation of PTEN, the inhibition of the epithelial to mesenchymal transition (EMT), a reduction in Nestin, and increases in Tuj1 and GFAP differentiation neuronal markers [15].…”

“…Its overexpression promotes cell motility and cancer progression and metastasis [22,23]. Prune-1 is a multi-domain adaptor protein with an unfolded domain, allowing interactions with several binding partners and the modulation of different signaling cascades, including WNT and TGF-β signaling, and serves as nodal points in the regulation of many cellular activities [24,25] The WNT and TGF-β pathways are cell-cell signaling systems that control a plethora of processes, from embryonic development and cell proliferation, differentiation and migration, to tissue homeostasis, stem cell behavior, tissue regeneration, and cancers [26]. TGF-β is also known to regulate the systemic immune surveillance of the tumor host by controlling immune responses, and it maintains immune homeostasis through its impact on proliferation, differentiation, and in the tumor microenvironment (TME) of multiple immune cell lineages [27].…”