JBC INTERFERin siRNA transfection reagent

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 QUICK SEARCH:   [advanced]


     


Originally published In Press as doi:10.1074/jbc.M508533200 on January 30, 2006

J. Biol. Chem., Vol. 281, Issue 17, 11923-11932, April 28, 2006
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
281/17/11923    most recent
M508533200v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yeung, B. H. Y.
Right arrow Articles by Sinicrope, F. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yeung, B. H. Y.
Right arrow Articles by Sinicrope, F. A.
Social Bookmarking
 Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

PS-341 (Bortezomib) Induces Lysosomal Cathepsin B Release and a Caspase-2-dependent Mitochondrial Permeabilization and Apoptosis in Human Pancreatic Cancer Cells*

Bonnie H. Y. Yeung, Der-Chen Huang, and Frank A. Sinicrope1

From the Divisions of Gastroenterology and Hepatology and Oncology, Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905

PS-341 (bortezomib) is a potent and reversible proteosome inhibitor that functions to degrade intracellular polyubiquitinated proteins. PS-341 induces apoptosis and has shown broad antitumor activity with selectivity for transformed cells. We studied the effect of PS-341 on lysosomal and mitochondrial permeabilization, including the role of caspase-2 activation in apoptosis induction in the BxPC-3 human pancreatic carcinoma cell line. PS-341 induced a dose-dependent apoptosis in association with reactive oxygen species generation and cleavage of caspase-2 to its 33- and 14-kDa fragments. PS-341 disrupted lysosomes with redistribution of cathepsin B to the cytosol, as shown using fluorescence confocal microscopy, that was blocked by the free radical scavenger tiron but not by a caspase-2 inhibitor (benzyloxycarbonyl (Z)-VDVAD-fluoromethyl ketone (FMK)). PS-341-induced caspase-2 activation was attenuated by a selective pharmacological inhibitor of cathepsin B (R-3032), suggesting that cathepsin B release occurs upstream of caspase-2. PS-341-induced mitochondrial depolarization was attenuated by Z-VDVAD-FMK, tiron, and an inhibitor of the mitochondrial permeability transition pore (bongkrekic acid). Regulation of mitochondrial permeability by caspase-2 was confirmed using caspase-2 small interfering RNA. PS-341-induced cytochrome c release and phosphatidylserine externalization were attenuated by Z-VDVAD-FMK and partially by R-3032. PS-341 activated the BH3-only proteins Bik and Bim and down-regulated Bcl-2 and Bcl-xL mRNA and protein expression. Taken together, PS-341 induces lysosomal cathepsin B redistribution upstream of caspase-2. Caspase-2 activation regulates PS-341-induced mitochondrial depolarization and apoptosis, suggesting that caspase-2 can serve as a link between lysosomal and mitochondrial permeabilization.


Received for publication, August 3, 2005 , and in revised form, January 23, 2006.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St., SW, Rochester, MN 55905. Fax: 507-266-0350; E-mail: sinicrope.frank{at}mayo.edu.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
Molecular Cancer TherapeuticsHome page
H. Gu, X. Chen, G. Gao, and H. Dong
Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells
Mol. Cancer Ther., August 1, 2008; 7(8): 2298 - 2307.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
M. A. Park, A. Yacoub, M. Rahmani, G. Zhang, L. Hart, M. P. Hagan, S. K. Calderwood, M. Y. Sherman, C. Koumenis, S. Spiegel, et al.
OSU-03012 Stimulates PKR-Like Endoplasmic Reticulum-Dependent Increases in 70-kDa Heat Shock Protein Expression, Attenuating Its Lethal Actions in Transformed Cells
Mol. Pharmacol., April 1, 2008; 73(4): 1168 - 1184.
[Abstract] [Full Text] [PDF]


Home page
Molecular Cancer TherapeuticsHome page
A. Yacoub, M. A. Park, P. Gupta, M. Rahmani, G. Zhang, H. Hamed, D. Hanna, D. Sarkar, I. V. Lebedeva, L. Emdad, et al.
Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells
Mol. Cancer Ther., February 1, 2008; 7(2): 297 - 313.
[Abstract] [Full Text] [PDF]


Home page
J. Virol.Home page
T. Subramanian, S. Vijayalingam, E. Lomonosova, L.-j. Zhao, and G. Chinnadurai
Evidence for Involvement of BH3-Only Proapoptotic Members in Adenovirus-Induced Apoptosis
J. Virol., October 1, 2007; 81(19): 10486 - 10495.
[Abstract] [Full Text] [PDF]


Home page
Mol. Cell. Biol.Home page
M. Rahmani, E. M. Davis, T. R. Crabtree, J. R. Habibi, T. K. Nguyen, P. Dent, and S. Grant
The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress
Mol. Cell. Biol., August 1, 2007; 27(15): 5499 - 5513.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
A. M. Fribley, B. Evenchik, Q. Zeng, B. K. Park, J. Y. Guan, H. Zhang, T. J. Hale, M. S. Soengas, R. J. Kaufman, and C.-Y. Wang
Proteasome Inhibitor PS-341 Induces Apoptosis in Cisplatin-resistant Squamous Cell Carcinoma Cells by Induction of Noxa
J. Biol. Chem., October 20, 2006; 281(42): 31440 - 31447.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.