The small molecule SI113 hinders epithelial-to-mesenchymal transition and subverts cytoskeletal organization in human cancer cells

Claudia Abbruzzese, Silvia Matteoni, Michele Persico, Barbara Ascione, Silvia Schenone, Francesca Musumeci, Rosario Amato, Nicola Perrotti, Paola Matarrese, Marco G. Paggi

Research output: Contribution to journalArticlepeer-review

Abstract

The small molecule SI113 is an inhibitor of the kinase activity of SGK1, a key biological regulator acting on the PI3K/mTOR signal transduction pathway. Several studies demonstrate that this compound is able to strongly restrain cancer growth in vitro and in vivo, alone or in associative antineoplastic treatments, being able to elicit an autophagic response, either cytotoxic or cytoprotective. To elucidate more exhaustively the molecular mechanisms targeted by SI113, we performed activity-based protein profiling (ABPP) proteomic analysis using a kinase enrichment procedure. This technique allowed the identification via mass spectrometry of novel targets of this compound, most of them involved in functions concerning cell motility and cytoskeletal architecture. Using a glioblastoma multiforme, hepatocarcinoma and colorectal carcinoma cell line, we recognized an inhibitory effect of SI113 on cell migration, invading, and epithelial-to-mesenchymal transition. In addition, these cancer cells, when exposed to this compound, showed a remarkable subversion of the cytoskeletal architecture characterized by F-actin destabilization, phospho-FAK delocalization, and tubulin depolimerization. These results were definitely concordant in attributing to SI113 a key role in hindering cancer cell malignancy and, due to its negligible in vivo toxicity, can sustain performing a Phase I clinical trial to employ this drug in associative cancer therapy.
Original languageEnglish
Pages (from-to)22529-22542
Number of pages14
JournalJournal of Cellular Physiology
Volume234
Issue number12
DOIs
Publication statusPublished - Dec 1 2019

Keywords

  • activity-based protein profiling (ABPP)
  • cytoskeleton
  • epithelial-to-mesenchymal transition
  • kinase inhibitors
  • SI113

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