title: Preferential cytotoxicity of bortezomib toward hypoxic tumor cells via overactivation of endoplasmic reticulum stress pathways.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6072, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Fels
authors.forename: Jiangbin
authors.initials: J
authors.lastname: Ye
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Segan
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kridel
authors.forename: Michael
authors.initials: M
authors.lastname: Spiotto
authors.forename: Michael
authors.initials: M
authors.lastname: Olson
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009336:Necrosis; D011480:Protease Inhibitors / Q000494:pharmacology*; D017510:Protein Folding; D011719:Pyrazines / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D013312:Stress, Physiological / Q000187:drug effects*; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; D000069286:Bortezomib