Exploring a Role for Nucleophosmin-1 in Homing of Breast and Prostate Cancers to the Bone

Abstract

Title: Exploring a Role for Nucleophosmin-1 in Homing of Breast and Prostate Cancers to the Bone Background: Metastasis is the most devastating aspect of cancer, accounting for 90% of cancer-related mortality. Despite intensive research efforts to untie the molecular paradigms of metastasis, this process is still incurable and requires in-depth exploration. According to international databases, prostate and breast cancers (PC and BC) classify among the leading cancers globally, with a frightening increase in mortality to incidence ratio in the Middle East. Bone is the preferential site of metastasis for both PC and BC. Others and we described a critical role for Nucleophosmin-1 (NPM1), a pleiotropic chaperone protein, in several cancers. NPM1 is overexpressed in PC and in triple negative breast cancer (TNBC), associating with patients’ poor survival. Of several NPM1 functions, ribosomal biogenesis influences crucial steps in metastasis.

Aim: Our research focused on exploring the role of NPM1 and related pathways in PC and BC. We particularly assessed ribosomal machinery and epithelial mesenchymal transition (EMT), upon downregulation of NPM1.

Methods: BC (MDA-MB-231 and MCF-7) and PC (PC3 and LNCaP) cells were used in our study. Ribosomal biogenesis was evaluated by real-time PCR. NPM1 expression was downregulated in MDA-MB-231 and PC3 cells, using small interference and short hairpin RNA. Key proteins interacting with NPM1 or involved in the EMT process were evaluated by western-blotting and confocal microscopy assays upon down-regulation of NPM1.

Results: We demonstrated that downregulation of NPM1 in BC and PC cells with high metastatic potential (MDA-MB-231 and PC3) reduced their proliferation. Moreover, NPM1 knock-down in these cell lines reduced the protein expression levels of SENP3, increased the protein levels of ARF, and reduced rRNA synthesis. Strikingly, BC and PC cells exhibited a more differentiated phenotype (with higher expression of epithelial markers) upon downregulation of NPM1, as compared to the mesenchymal phenotype of these high metastatic tumors.

Conclusion: Our results highlight a role for NPM1 in the mesenchymal phenotype of PC and BC metastatic cancer cells and provide insights on the implication of NPM1 and its induced ribosomal biogenesis in the metastatic phenotype of these highly aggressive cancers.