Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types

• Published in: PloS one Vol. 7; no. 11; p. e47519
• Main Authors: Sermeus, Audrey, Genin, Marie, Maincent, Amélie, Fransolet, Maude, Notte, Annick, Leclere, Lionel, Riquier, Hélène, Arnould, Thierry, Michiels, Carine
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 05.11.2012; Public Library of Science (PLoS)
• Subjects: Abundance; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Bcl-2 protein; BIM protein; Biochemistry; Biology; Cancer; Cancer therapies; Cell cycle; Cell death; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell Line, Tumor; Cellular biology; Chemoresistance; Chemotherapy; DNA Damage - genetics; Drugs; Electrophoretic mobility; Etoposide; Etoposide - pharmacology; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Silencing - drug effects; Health aspects; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Kinases; Laboratories; Lymphoma; Medicine; Models, Biological; Modulation; Mortality; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; p53 Protein; Paclitaxel - pharmacology; Phosphorylation; Post-translation; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Translation; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Tumors
• DOI: 10.1371/journal.pone.0047519
• ISSN: 1932-6203

Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIM(EL). BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and -independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.