PC-SPES down-regulates COX-2 via inhibition of NF-kappaB and C/EBPbeta in non-small cell lung cancer cells.
Aberrant expression of COX-2 occurs in many types of malignancies including colon and lung cancers, and is implicated in development and progression of cancer. The molecular mechanisms associated with aberrant expression of COX-2 in lung cancer cells remain to be fully elucidated. In this study, we found that non-small cell lung cancer (NSCLC) NCI-H520 and NCI-H460 cells constitutively expressed COX-2 and produced prostaglandin E2 (PGE2) as measured by Western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Reporter assays showed that transcriptional regulation of COX-2 was blunted when either the NF-IL6 (C/EBPbeta) or nuclear factor-kappaB (NF-kappaB) binding site in the COX-2 promoter was mutated, suggesting that C/EBPbeta and NF-kappaB transcription factors have an important role in aberrant expression of COX-2 in these lung cancer cells. In addition, the eight herbal mixture PC-SPES (Lot. 5431219) caused growth arrest and apoptosis of NCI-H520 and NCI-H460 cells in association with blockade of NF-kappaB and down-regulation of C/EBPbeta, resulting in down-regulation of COX-2 and PGE2 in these cells. On the other hand, PC-SPES up-regulated the level of C/EBPbeta in these cells. Taken together, C/EBPbeta and NF-kappaB may be promising molecular targets for COX-2 inhibition in lung cancer cells. PC-SPES might be useful in the adjuvant setting for the treatment of individuals with resected NSCLC as well as other types of cancer in which COX-2 is activated.
Ikezoe
Takayuki
T
Division of Hematology/Oncology and Thoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. ikezoet@med.kochi-ms.ac.jp
Yang
Yang
Y
Saitoh
Takayuki
T
Heber
David
D
McKenna
Robert
R
Taguchi
Hirokuni
H
Koeffler
H Phillip
HP
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D022782:CCAAT-Enhancer-Binding Protein-beta; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; C114209:herbal preparation PC-SPES