Cancer research (Chicago, Ill.), 2008-02, Vol.68 (4), p.1162-1169
2008
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Details
- Autor(en) / Beteiligte
- Titel
- A Selective Phosphatase of Regenerating Liver Phosphatase Inhibitor Suppresses Tumor Cell Anchorage-Independent Growth by a Novel Mechanism Involving p130Cas Cleavage
- Ist Teil von
- Cancer research (Chicago, Ill.), 2008-02, Vol.68 (4), p.1162-1169
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2008
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser(15)), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.CAN-07-2349Titel-ID: cdi_proquest_miscellaneous_70301526
- Format
- –
- Schlagworte
- Amino Acid Sequence, Animals, Anoikis - drug effects, Antineoplastic agents, Biological and medical sciences, Cell Adhesion - drug effects, Cell Adhesion - physiology, Cell Growth Processes - drug effects, Cell Line, Tumor, Crk-Associated Substrate Protein - metabolism, Endothelial Cells - drug effects, Enzyme Inhibitors - pharmacology, HeLa Cells, HT29 Cells, Humans, Medical sciences, Mice, Molecular Sequence Data, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - genetics, Neoplasms - drug therapy, Neoplasms - metabolism, Neoplasms - pathology, Pharmacology. Drug treatments, Protein Tyrosine Phosphatases - antagonists & inhibitors, Protein Tyrosine Phosphatases - genetics, Pyridines - pharmacology, RNA, Small Interfering - genetics, Tumors, Xenograft Model Antitumor Assays