Implication of proteasome in estrogen receptor degradation

Abstract

In MCF-7 breast cancer cells, estradiol (E P ) and pure antiestrogen RU 58668 down-regulate the estrogen receptor (ER). Interestingly, the protein synthesis inhibitor cycloheximide (CHX) abrogated solely the effect of E P suggesting a selective difference in the degradation of the receptor induced by estrogenic and antiestrogenic stimulations. A panel of lysosome inhibitors (i.e. bafilomycin, chloroquine, NH R Cl, and monensin), calpain inhibitors (calpastatin and PD 150606) and proteasome inhibitors (lactacystin and proteasome inhibitor I) were tested to assess this hypothesis. Among all inhibitors tested, lactacystin and proteasome inhibitor I were the sole inhibitors to abrogate the elimination of the receptor induced by both E P and RU 58668; this selective effect was also recorded in cells prelabeled with [Q H]tamoxifen aziridine before exposure to these ligands. Hence, differential sensitivity to CHX seems to be linked to the different mechanisms which target proteins for proteasomemediated destruction. Moreover, the two tested proteasome inhibitors produced a slight increase of ER concentration in cells not exposed to any ligand, suggesting also the involvement of proteasome in receptor turnover.z 1999 Federation of European Biochemical Societies.

Capacity of type I and II ligands to confer to estrogen receptor alpha an appropriate conformation for the recruitment of coactivators containing a LxxLL motif—Relationship with the regulation of receptor level and ERE-dependent transcription in MCF-7 cells

“…Previous studies have revealed that cycloheximide (CHX) at 50 µM abrogates E 2 -induced ERα degradation by the ubiquitin-proteasome system [33][34][35]. Our investigations extended this finding to all ligands able to induce LxxLL-motif recruitment (data not shown).…”

Antiestrogens: structure-activity relationships and use in breast cancer treatment

“…1991, Dauvois et al . 1992, El Khissiin & Leclercq 1999, Wijayaratne & McDonnell 2001). However, despite the pure antiestrogenic character of fulvestrant, it did not compare advantageously with tamoxifen when used as a first-line therapy for advanced or metastatic breast cancer (Howell et al .…”

Calmodulin, a regulatory partner of the estrogen receptor alpha in breast cancer cells

“…Studies conducted in various laboratories have demonstrated the implication of the ubiquitin-proteasome system (UPS) in the elimination of the mature receptor which has achieved transactivation and has become functionally obsolete (Alarid et al, 1999;El Khissiin, Leclercq, 1999;Laïos et al, 2005;Nawaz et al, 1999a;Wijayaratne, McDonnell, 2001). Natural and pharmacological ligands either accelerate (estrogens, pure antiestrogens) or reduce (partial antiestrogens) the proteasomal degradation of ERα (Laïos et al, 2005;Read et al, 1989;Wijayaratne, McDonnell, 2001) by selecting UPS with high or low degradation rate.…”