Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells

2009 ◽  
Vol 219 (2) ◽  
pp. 314-323 ◽  
Author(s):  
Federica Rizzi ◽  
Alessandro Emanuele Caccamo ◽  
Lucia Belloni ◽  
Saverio Bettuzzi
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Half Life ◽  
Prostate Cancer Cells ◽  
Ubiquitinated Protein ◽  
Short Half Life

718 AMG 509, a STEAP1 x CD3 bispecific XmAb® 2+1 immune therapy, exhibits avidity-driven binding and preferential killing of high STEAP1-expressing prostate and Ewing sarcoma cancer cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A760-A760
Author(s):  
Cong Li ◽  
Madeline Fort ◽  
Lingming Liang ◽  
Gregory Moore ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cell Surface ◽  
Cancer Cells ◽  
Ewing Sarcoma ◽  
Half Life ◽  
Laboratory Animal ◽  
Prostate Cancer Cells ◽  
Animal Care

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) and Ewing sarcoma (EWS) are diseases for which immune therapies could potentially provide benefit. STEAP1 (Six Transmembrane Epithelial Antigen of the Prostate 1) is a cell surface protein with elevated expression in mCRPC 1 and EWS.2MethodsWe designed AMG 509, a novel, half-life extended, STEAP1 x CD3 XmAb® 2+1 bispecific antibody to induce T cell-mediated cytotoxicity against STEAP1-expressing cancer cells. AMG 509 contains two identical anti-STEAP1 Fab domains, an anti-CD3 scFv domain, and an effectorless Fc domain that extends serum half-life. We characterized STEAP1 expression in normal and tumor tissues by immunohistochemistry, and we assessed the pharmacological properties of AMG 509 including binding, T cell-mediated redirected lysis, and in vivo antitumor activity.ResultsWe detected high STEAP1 surface expression on 80% of primary prostate tumors (n=88), 89% of mCRPC lesions (n=114), including 84% of mCRPC bone metastases (n=31), and 63% of EWS samples (n=35). In contrast, in normal tissues (n=72), low STEAP1 expression was detected in only six other tissues, including the normal prostate. AMG 509 bound to recombinant human CD3ε with a KD of 27.6 nM, and it bound specifically to 293T cells transfected with human STEAP1 with an EC50 of 3.8 nM. AMG 509 triggered potent T cell-redirected lysis of STEAP1-positive cancer cells, with a median EC50 of 37 pM across 19 cancer cell lines that endogenously express various levels of STEAP1. AMG 509-mediated cytotoxicity was specific, as it showed no activity against prostate cancer cells in which STEAP1 was knocked out. AMG 509 was 65-fold more potent in inducing the redirected lysis of prostate cancer cells in vitro than an XmAb® molecule with a single anti-STEAP1 Fab domain. AMG 509 had greater cytotoxic activity against high STEAP1-expressing cancer cells than against low STEAP1-expressing cancer cells, and it had minimal activity against normal cells. This preferential killing of high STEAP1-expressing cells is likely driven by the avidity conferred by the dual STEAP1-binding domains, a feature that may help reduce off-target effects in the clinic. In vivo, AMG 509 induced robust anti-tumor activity in prostate cancer and EWS mouse xenograft models, with concomitant CD8+ T-cell activation and expansion in tumors.ConclusionsAMG 509 is a specific, first-in-class T cell-recruiting antibody with avidity-driven activity against STEAP1-positive malignancies. AMG 509 is currently being evaluated for safety, pharmacokinetics, and efficacy in a phase 1, first-in-human study in patients with mCRPC (NCT04221542).AcknowledgementsThe authors acknowledge Micah Robinson, PhD of Amgen Inc. for medical writing support.Trial RegistrationClinicalTrials. gov Identifier: NCT04221542Ethics ApprovalAll animal experimental protocols were approved by an Institutional Animal Care and Use Committee (IACUC protocol number 2015-01243) and were conducted in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) (Amgen) or the standards of the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (IACUC protocol number 15015x) in a facility certified with an Office of Laboratory Animal Welfare (OLAW) (UTHSA).ReferencesGrunewald TGP, Ranft A, Esposito I, Silva-Buttkus P da, Aichler M, Baumhoer D, Schaefer KL, Ottaviano L, Poremba C, Jundt G, Jurgens H, Dirksen U, Richter GHS, Burdach S. High STEAP1 expression is associated with improved outcome of Ewing’s sarcoma patients. Ann Oncol 2012; 23:2185–2190.Hubert RS, Vivanco I, Chen E, Rastegar S, Leong K, Mitchell SC, Madraswala R, Zhou Y, Kuo J, Raitano AB, Jakobvits A, Saffran SC, Afar DE. STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc Natl Acad Sci USA 1999;96:14523–14528.

scholarly journals Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 363
Author(s):  
Teddy Kamata ◽  
Chun-Song Yang ◽  
Tiffany A. Melhuish ◽  
Henry F. Frierson Jr. ◽  
David Wotton ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Half Life ◽  
Catalytic Domain ◽  
Prostate Cancer Cells ◽  
Rapid Turnover ◽  
Direct Target Gene ◽  
Post Transcriptional Regulation ◽  
Adp Ribosyltransferase

Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze ADP-ribosylation and play critical roles in normal and disease settings. The PARP family member, PARP7, is a mono-ADP-ribosyltransferase that has been suggested to play a tumor suppressive role in breast, ovarian, and colorectal cancer. Here, we have investigated how androgen signaling regulates PARP7 homeostasis in prostate cancer cells, where PARP7 is a direct target gene of AR. We found that the PARP7 protein is extremely short-lived, with a half-life of 4.5 min. We show that in addition to its transcriptional regulation by AR, PARP7 is subject to androgen-dependent post-transcriptional regulation that increases its half-life to 25.6 min. This contrasts with PARP1, PARP2, PARP9, and PARP14, which do not display rapid turnover and are not regulated by androgen signaling. Androgen- and AR-dependent stabilization of PARP7 leads to accumulation in the nucleus, which we suggest is a major site of action. Mutations in the catalytic domain, the Cys3His1 zinc finger, and WWE (tryptophan–tryptophan–glutamate) domains in PARP7 each reduce the degradation rate of PARP7, suggesting the overall structure of the protein is tuned for its rapid turnover. Our finding that PARP7 is regulated by AR signaling both transcriptionally and post-transcriptionally in prostate cancer cells suggests the dosage of PARP7 protein is subject to tight regulation.

279: Inhibition of Cyclooxygenase-2 Pathway Overcomes the Heat-Resistance in Prostate Cancer Cells

2007 ◽  
Vol 177 (4S) ◽  
pp. 93-93
Author(s):  
Makoto Sumitomo ◽  
Kenji Kuroda ◽  
Takako Asano ◽  
Akio Horiguchi ◽  
Keiichi Ito ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Heat Resistance ◽  
Cancer Cells ◽  
Cyclooxygenase 2 ◽  
Prostate Cancer Cells

609: Effects of Sirna and Phytoestrogen Treatments on the Expression of Genes Regulated through the Androgen Receptor of Lncap Prostate Cancer Cells

2004 ◽  
Vol 171 (4S) ◽  
pp. 162-162
Author(s):  
Paul Thelen ◽  
Michal Grzmil ◽  
Iris E. Eder ◽  
Barbara Spengler ◽  
Peter Burfeind ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Prostate Cancer Cells ◽  
Expression Of Genes
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