Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.

Abstract

Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.

• Authors: A Rodriguez-Gonzalez, K Cyrus, M Salcius, K Kim, C M Crews, R J Deshaies, K M Sakamoto
• Journal: Oncogene (Oncogene) Vol. 27 Issue 57 Pg. 7201-11 (Dec 04 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18794799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Estrogen Receptor alpha
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Androgen
• Receptors, Steroid
• Recombinant Fusion Proteins
• Dihydrotestosterone
• Estradiol
• Proteasome Endopeptidase Complex

Topics

• Antineoplastic Agents (administration & dosage, chemistry)
• Blotting, Western
• Breast Neoplasms (drug therapy, metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dihydrotestosterone (administration & dosage, metabolism)
• Drug Delivery Systems (methods)
• Estradiol (administration & dosage, metabolism)
• Estrogen Receptor alpha (drug effects, metabolism)
• Female
• Flow Cytometry
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (administration & dosage, chemistry)
• Male
• Neoplasms, Hormone-Dependent (drug therapy, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism)
• Proteasome Endopeptidase Complex (drug effects)
• Receptors, Androgen (drug effects, metabolism)
• Receptors, Steroid (drug effects, metabolism)
• Recombinant Fusion Proteins (administration & dosage, chemistry)
• Ubiquitination (physiology)