This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fels, D. R. Articles by Koumenis, C. Search for Related Content PubMed PubMed Citation Articles by Fels, D. R. Articles by Koumenis, C.

Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways

¹ Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ² Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and ³ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California

Requests for reprints: Constantinos Koumenis, Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6072. Phone: 215-898-0076; Fax: 215-898-0090; E-mail: koumenis{at}xrt.upenn.edu.

Key Words: Hypoxia • UPR • proteasome inhibitor • bortezomib • autophagy

Hypoxia is a dynamic feature of the tumor microenvironment that contributes to drug resistance and cancer progression. We previously showed that components of the unfolded protein response (UPR), elicited by endoplasmic reticulum (ER) stress, are also activated by hypoxia in vitro and in vivo animal and human patient tumors. Here, we report that ER stressors, such as thapsigargin or the clinically used proteasome inhibitor bortezomib, exhibit significantly higher cytotoxicity toward hypoxic compared with normoxic tumor cells, which is accompanied by enhanced activation of UPR effectors in vitro and UPR reporter activity in vivo. Treatment of cells with the translation inhibitor cycloheximide, which relieves ER load, ameliorated this enhanced cytotoxicity, indicating that the increased cytotoxicity is ER stress–dependent. The mode of cell death was cell type–dependent, because DLD1 colorectal carcinoma cells exhibited enhanced apoptosis, whereas HeLa cervical carcinoma cells activated autophagy, blocked apoptosis, and eventually led to necrosis. Pharmacologic or genetic ablation of autophagy increased the levels of apoptosis. These results show that hypoxic tumor cells, which are generally more resistant to genotoxic agents, are hypersensitive to proteasome inhibitors and suggest that combining bortezomib with therapies that target the normoxic fraction of human tumors can lead to more effective tumor control. [Cancer Res 2008;68(22):9323–30]

This article has been cited by other articles:

				S. Tardito, C. Isella, E. Medico, L. Marchio, E. Bevilacqua, M. Hatzoglou, O. Bussolati, and R. Franchi-Gazzola The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells J. Biol. Chem., September 4, 2009; 284(36): 24306 - 24319. [Abstract] [Full Text] [PDF]

				M. Milani, T. Rzymski, H. R. Mellor, L. Pike, A. Bottini, D. Generali, and A. L. Harris The Role of ATF4 Stabilization and Autophagy in Resistance of Breast Cancer Cells Treated with Bortezomib Cancer Res., May 15, 2009; 69(10): 4415 - 4423. [Abstract] [Full Text] [PDF]