title: 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.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urology, Osaka Medical College, Osaka, Japan.
authors.forename: Naokazu
authors.initials: N
authors.lastname: Ibuki
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mazyar
authors.initials: M
authors.lastname: Ghaffari
authors.affiliation: TyrNovo Ltd., Herzliya, Israel. Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Reuveni
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Mitali
authors.initials: M
authors.lastname: Pandey
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Urology, Osaka Medical College, Osaka, Japan.
authors.forename: Haruhito
authors.initials: H
authors.lastname: Azuma
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
authors.affiliation: The Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. mcox@prostatecentre.com.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cox
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D000077143:Docetaxel; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009919:Orchiectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D020032:Tyrphostins; D000077143:Docetaxel; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D048049:Extracellular Signal-Regulated MAP Kinases