550 HEAT SHOCK PROTEIN 27 INHIBITION ACTIVATES THE UNFOLD PROTEIN RESPONSE PATHWAY THROUGH INHIBITION OF PROTEASOME ACTIVITY IN PROSTATE CANCER
Bibliographic record
Abstract
You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2010550 HEAT SHOCK PROTEIN 27 INHIBITION ACTIVATES THE UNFOLD PROTEIN RESPONSE PATHWAY THROUGH INHIBITION OF PROTEASOME ACTIVITY IN PROSTATE CANCER Junya Furukawa, Amina Zoubeidi, Eliana Beraldi, and Martin Gleave Junya FurukawaJunya Furukawa More articles by this author , Amina ZoubeidiAmina Zoubeidi More articles by this author , Eliana BeraldiEliana Beraldi More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.770AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hsp27 is a stress-activated, multifunctional chaperone that inhibits treatment-induced apoptosis and is highly expressed in castrate-resistant prostate cancer. Hsp27 is induced by accumulation of unfolded protein aggregates following various stress conditions, and facilitates folding of proteins to their native state or degrading misfolded proteins via the ubiquitin-proteasome pathway (UPP). The specific signaling that occurs between the endoplasmic reticulum (ER) and the nucleus in response to ER stress is known as the unfolded protein response (UPR). During the UPR, accumulated unfolded protein is either correctly refolded or degraded by the UPP, but when unfolded protein levels exceed a threshold, damaged cells are committed to cell death. We hypothesize that inhibition of Hsp27 will enhance ER stress and treatment-induced cancer cell death by increasing unfolded protein burden. We set out to characterize the role of Hsp27 in ER stress and UPR in prostate cancer. METHODS Effects of Hsp27 silencing using siRNA or proteasome inhibition using MG132 on PC3 cell apoptosis and putative targets of UPR were compared. Proteasome activity was measured using fluorescent substrate of proteasome in Hsp27 inhibited or overexpressed PC3 cells. RESULTS Hsp27 expression and other components of the UPR was activated in PC-3 cells after treatment with MG132 with accumulation of ubiquitinated proteins. Hsp27 knockdown was associated with decreased proteasome activity, increased ubiquitinated protein levels, and activation of UPR, similar to that seen with MG132. Hsp27 silencing significantly reduced PC3 cell growth and induced apoptosis coincident with UPR activation. In contrast, Hsp27 overexpressing PC3 cells exhibited increased proteasome activity and resistance to MG-132 induced cell death and UPR activation compared to control cells. CONCLUSIONS These results suggest that Hsp27 enhances the catalytic activity of the proteasome and increases the degradation rate of ubiquitinated proteins. Moreover, inhibition of Hsp27 induces prostate cancer cell death in part via ER stress and UPR death pathway and represents an important mechanism to target for anti-cancer therapies. Vancouver, Canada© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e216 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Junya Furukawa More articles by this author Amina Zoubeidi More articles by this author Eliana Beraldi More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".