Unraveling the protein kinase C/NDRG1 signaling network in breast cancer
N-myc downstream-regulated gene 1 (NDRG1) is a member of the NDRG family of intracellular proteins and plays a central role in a wide range of biological processes including stress response, differentiation, and metabolism. The overexpression of NDRG1 is an indicator of poor prognosis in various types of cancer. Here, we found that NDRG1 is an independent prognostic marker of poor outcome in breast cancer (BC). Analysis of the TCGA dataset showed a significant positive correlation between NDRG1 and PRKCA expression, suggesting a mechanistic role of protein kinase C (PKC) in the regulation of NDRG1. We then assessed the hypothesis that PKC might modulate the activity of NDRG1, and observed that different acute stress conditions converging on PKC activation lead to enhanced NDRG1 expression. This mechanism was found to be specific for NDRG1 as the expression of other NDRG members was not affected. Moreover, CRISPR-based inhibition of NDRG1 expression was obtained in a BC cell line, and showed that this protein is a key driver of BC cell invasion through the Rho-associated coiled-coil containing protein kinase 1 (ROCK1)/phosphorylated cofilin pathway that regulates stress fiber assembly, and the modulation of extracellular matrix reorganization related genes. Together, our findings highlight the potential of NDRG1 as a new BC biomarker and uncover a novel mechanism of regulation of NDRG1 expression that might lead to innovative therapeutic strategies.
Authors
- Andrea Tinelli (ORCID: https://orcid.org/0000-0001-8426-8490)
- Eugenio Fonzi (ORCID: https://orcid.org/0000-0001-8389-8220)
- Stefano Tacconi (ORCID: https://orcid.org/0000-0001-7424-1251)
- Francesca Pirini (ORCID: https://orcid.org/0000-0002-7629-2439)
- Domenico Sergi (ORCID: https://orcid.org/0000-0002-3001-410X)
- Ludovica Pantalone (ORCID: https://orcid.org/0000-0002-4212-8251)
- Maurizio Puccetti (ORCID: https://orcid.org/0009-0001-1476-3194)
- Anna Maria Giudetti (ORCID: https://orcid.org/0000-0002-9204-040X)
- Isabelle Fournier (ORCID: https://orcid.org/0000-0003-1096-5044)
- Luisa Siculella (ORCID: https://orcid.org/0000-0002-6890-3674)
- Sara Bravaccini (ORCID: https://orcid.org/0000-0002-0075-8538)
- Simona De Summa (ORCID: https://orcid.org/0000-0001-9607-3754)
- Michel Salzet (ORCID: https://orcid.org/0000-0003-4318-0817)
- Michela Tebaldi (ORCID: https://orcid.org/0000-0003-0717-2748)
- Eleonora Stanca (ORCID: https://orcid.org/0000-0002-0087-1231)
- Francesco Alfredo Zito (ORCID: https://orcid.org/0000-0003-4140-4020)
- Marco Trerotola (ORCID: https://orcid.org/0000-0003-1855-7002)
- Antonio Gaballo (ORCID: https://orcid.org/0000-0003-2104-1568)
- Laura Schirosi (ORCID: https://orcid.org/0000-0001-7898-1273)
- Concetta Saponaro (ORCID: https://orcid.org/0000-0002-8196-3583)
- Maurizio Ronci (ORCID: https://orcid.org/0000-0002-0797-6087)
- Soulaimane Aboulouard (ORCID: https://orcid.org/0000-0002-2045-4785)
- L. Magnani (ORCID: https://orcid.org/0000-0003-1864-4085)
- Debora Traversa (ORCID: https://orcid.org/0000-0003-0030-2394)
- Marina D’Amato (ORCID: https://orcid.org/0000-0003-0104-4323)
- Daniele Vergara (ORCID: https://orcid.org/0000-0002-2396-7674)
Institutions
- University of Salento (IT)
- Institute of Cancer Research (GB)
- Inserm (FR)
- University of Milan (IT)
- Università degli Studi di Enna Kore (IT)
- Breast Cancer Now (GB)
- Centre Hospitalier Universitaire de Lille (FR)
- University of Chieti-Pescara (IT)
- Istituto Nanoscienze (IT)
- Istituto di Nanotecnologia (IT)
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
- Istituto Tumori Bari (IT)
- Ospedale Vito Fazzi (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (FR)
- Imperial College London (GB)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Cell & Bioscience
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1186/s13578-024-01336-z
- Citations
- 4
- Primary Topic
- Mechanisms of cancer metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Ministero della Salute