The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer.

Abstract

Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer (CRPC) progression. Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from IGF1 receptor (IGF1R), insulin receptor, and other oncoproteins. This study demonstrates that IRS1/2 expression is increased in prostate cancer, and persists in CRPC. Furthermore, this study assesses the anticancer activity of NT157, a small molecule tyrphostin targeting IRS proteins, using androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2-M arrest in PC3 cells. NT157 also suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts, and suppressed PC3 tumor growth alone and in combination with docetaxel. This study reports the first preclinical proof-of-principle data that this novel small molecule tyrosine kinase inhibitor suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo. Demonstration that IRS expression can be increased in response to a variety of stressors that may lead to resistance or reduced effect of the therapies indicate that NT157-mediated IRS1/2 downregulation is a novel therapeutic approach for management of advanced prostate cancer.

• Authors: Naokazu Ibuki, Mazyar Ghaffari, Hadas Reuveni, Mitali Pandey, Ladan Fazli, Haruhito Azuma, Martin E Gleave, Alexander Levitzki, Michael E Cox
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 12 Pg. 2827-39 (Dec 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25267499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• IRS1 protein, human
• IRS2 protein, human
• Insulin Receptor Substrate Proteins
• Protein Kinase Inhibitors
• Taxoids
• Tyrphostins
• Docetaxel
• Phosphatidylinositol 3-Kinases
• Receptor, IGF Type 1
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Docetaxel
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Insulin Receptor Substrate Proteins (genetics, metabolism)
• Male
• Mice
• Orchiectomy
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proteolysis
• Receptor, IGF Type 1 (metabolism)
• Signal Transduction (drug effects)
• Taxoids (pharmacology)
• Tumor Burden (drug effects)
• Tyrphostins (pharmacology)
• Xenograft Model Antitumor Assays