Suppression of Lipogenesis via Reactive Oxygen Species-AMPK Signaling for Treating Malignant and Proliferative Diseases.

Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 100888899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7716 (Electronic) Linking ISSN: 15230864 NLM ISO Abbreviation: Antioxid Redox Signal Subsets: MEDLINE

Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., 1999-

AMP-Activated Protein Kinases/*genetics ; Arthritis, Rheumatoid/*drug therapy ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Lipogenesis/*genetics ; Sterol Regulatory Element Binding Protein 1/*genetics; Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/metabolism ; Arthritis, Rheumatoid/pathology ; Berberine/administration & dosage ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/genetics ; Fibroblasts/drug effects ; Fibroblasts/pathology ; Gefitinib ; Gene Expression Regulation/drug effects ; Humans ; Oxidation-Reduction ; Quinazolines/administration & dosage ; Quinazolines/adverse effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Synovial Fluid/drug effects ; Synovial Fluid/metabolism

Aims: Systemic diseases often have common characteristics. The aim of this study was to investigate the feasibility of targeting common pathological metabolism to inhibit the progression of malignant and proliferative diseases.
Results: Gefitinib-resistant (G-R) nonsmall-cell lung cancer (NSCLC) and rheumatoid arthritis (RA) were studied as conditions representative of malignant and proliferative diseases, respectively. Strong lipogenic activity and high expression of sterol regulatory element-binding protein 1 (SREBP1) were found in both G-R NSCLC cells and synovial fibroblasts from RA patients (RASFs). Berberine (BBR), an effective suppressor of SREBP1 and lipogenesis regulated through reactive oxygen species (ROS)/AMPK pathway, selectively inhibited the growth of G-R NSCLC cells and RASFs but not that of normal cells. It effectively caused mitochondrial dysfunction, activated ROS/AMPK pathway, and finally suppressed cellular lipogenesis and cell proliferation. Addition of ROS blocker, AMPK inhibitor, and palmitic acid significantly reduced the effect of BBR. In an in vivo study, treatment of BBR led to significant inhibition of mouse tumor xenograft growth and remarkably slowed down the development of adjuvant-induced arthritis in rats. Innovation and Conclusion: Targeting ROS/AMPK/lipogenesis signaling pathway selectively inhibited the growth of G-R NSCLC cells and the progress of RASFs in vitro and in vivo, which provides a new avenue for treating malignancies and proliferative diseases. Antioxid. Redox Signal. 28, 339-357.

Erratum in: Antioxid Redox Signal. 2019 Feb 1;30(4):710. (PMID: 30605373)

Keywords: ROS; SREBP1; berberine; gefitinib-resistant NSCLC; lipogenesis; rheumatoid arthritis

0 (Quinazolines)
0 (Reactive Oxygen Species)
0 (SREBF1 protein, human)
0 (Sterol Regulatory Element Binding Protein 1)
0I8Y3P32UF (Berberine)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
EC 2.7.11.31 (PRKAA1 protein, human)
S65743JHBS (Gefitinib)

Date Created: 20170701 Date Completed: 20180820 Latest Revision: 20220317

20240104

10.1089/ars.2017.7090

28665143