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Molecular and Cellular Biology, November 2004, p. 9695-9704, Vol. 24, No. 22
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.22.9695-9704.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Proteasome Inhibitor PS-341 Induces Apoptosis through Induction of Endoplasmic Reticulum Stress-Reactive Oxygen Species in Head and Neck Squamous Cell Carcinoma Cells

Andrew Fribley,1,2 Qinghua Zeng,1 and Cun-Yu Wang1,2*

Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences,1 Program in Oral Health Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan2

Received 25 April 2004/ Returned for modification 26 May 2004/ Accepted 28 July 2004

PS-341, also known as Velcade or Bortezomib, represents a new class of anticancer drugs which has been shown to potently inhibit the growth and/or progression of human cancers, including head and neck squamous cell carcinoma (HNSCC). Although it has been logically hypothesized that NF-{kappa}B is a major target of PS-341, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear. Here we found that PS-341 potently activated the caspase cascade and induced apoptosis in human HNSCC cell lines. Although PS-341 could inhibit NF-{kappa}B activation, the inhibition of NF-{kappa}B was not sufficient to initiate apoptosis in HNSCC cells. Using biochemical and microarray approaches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in HNSCC cells. The inhibition of ROS significantly suppressed caspase activation and apoptosis induced by PS-341. Consistently, PS-341 could not induce the ER stress-ROS in PS-341-resistant HNSCC cells. Taken together, our results suggest that in addition to the abolishment of the prosurvival NF-{kappa}B, PS-341 might directly induce apoptosis by activating proapoptotic ER stress-ROS signaling cascades in HNSCC cells, providing novel insights into the PS-341-mediated antitumor activity.

* Corresponding author. Mailing address: Laboratory of Molecular Signaling and Apoptosis, Department of Biologic and Materials Sciences, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Phone: (734) 615-4386. Fax: (734) 647-2110. E-mail: cunywang{at}umich.edu.

Molecular and Cellular Biology, November 2004, p. 9695-9704, Vol. 24, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.22.9695-9704.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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