Title |
Stressing the Ubiquitin-Proteasome System without 20S Proteolytic Inhibition Selectively Kills Cervical Cancer Cells
|
---|---|
Published in |
PLOS ONE, August 2011
|
DOI | 10.1371/journal.pone.0023888 |
Pubmed ID | |
Authors |
Ravi K. Anchoori, Saeed R. Khan, Thanasak Sueblinvong, Alicia Felthauser, Yoshie Iizuka, Riccardo Gavioli, Federica Destro, Rachel Isaksson Vogel, Shiwen Peng, Richard B. S. Roden, Martina Bazzaro |
Abstract |
Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | 17% |
North Macedonia | 1 | 17% |
Sweden | 1 | 17% |
Unknown | 3 | 50% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 5 | 83% |
Scientists | 1 | 17% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Canada | 1 | 2% |
Unknown | 58 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 10 | 17% |
Researcher | 10 | 17% |
Student > Master | 9 | 15% |
Student > Bachelor | 6 | 10% |
Student > Doctoral Student | 6 | 10% |
Other | 6 | 10% |
Unknown | 12 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 20 | 34% |
Medicine and Dentistry | 9 | 15% |
Biochemistry, Genetics and Molecular Biology | 7 | 12% |
Chemistry | 4 | 7% |
Nursing and Health Professions | 2 | 3% |
Other | 4 | 7% |
Unknown | 13 | 22% |