Reduction in BCL-2 levels by 26S proteasome inhibition with bortezomib is associated with induction of apoptosis in small cell lung cancer.
Overexpression of the anti-apoptotic protein BCL-2 is frequently observed in small cell lung cancers (SCLC) and is associated with chemoresistance. We examined the signaling pathways involved in upregulation of BCL-2 in SCLC, and whether inhibition of NF-kappaB using the 26S proteasome inhibitor bortezomib had any effect on BCL-2 levels or apoptosis. Mutation of a NF-kappaB site in the BCL-2 promoter reduced promoter activity to less than 20% of the wild-type promoter. Treatment with bortezomib resulted in decreased transcription of the BCL-2 promoter, decreased BCL-2 levels, and induced apoptosis. These data provide the necessary laboratory background for further investigation of bortezomib in the treatment of SCLC.
Mortenson
Melinda M
MM
Division of Surgical Oncology, Suite 3010, University of California, Davis Cancer Center, 4501 X Street, Sacramento, CA 95817, USA.
Schlieman
Michael G
MG
Virudachalam
Subbulakshmi
S
Lara
Primo N
PN
Gandara
David G
DG
Davies
Angela M
AM
Bold
Richard J
RJ
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018288:Carcinoma, Small Cell / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D008156:Luciferases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease