Blockade of TNF-α-induced NF-κB signaling pathway and anti-cancer therapeutic response of dihydrotanshinone I.
The nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. We identified dihydrotanshinone I as an inhibitor of NF-κB activation through our research on Salvia miltiorrhiza Bunge. In this study, we found that dihydrotanshinone I significantly inhibited the expression of NF-κB reporter gene induced by TNF-α in a dose-dependent manner. And dihydrotanshinone I also inhibited TNF-α induced phosphorylation and degradation of IκBα, phosphorylation and nuclear translocation of p65. Furthermore, pretreatment of cells with this compound prevented the TNF-α-induced expression of NF-κB target genes, such as anti-apoptosis (cIAP-1 and FLIP), proliferation (COX-2), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-α, IL-6, and MCP1). We also demonstrated that dihydrotanshinone I potentiated TNF-α-induced apoptosis. Moreover, dihydrotanshinone I significantly impaired activation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK/SAPK). In vivo studies demonstrated that dihydrotanshinone I suppressed the growth of HeLa cells in a xenograft tumor model, which could be correlated with its modulation of TNF-α production. Taken together, dihydrotanshinone I could be a valuable candidate for the intervention of NF-κB-dependent pathological conditions such as inflammation and cancer.
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Fei
F
Wang
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Juan
J
Ma
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Ke Si
KS
Wang
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Chunliu
C
Mi
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Jung Joon
JJ
Lee
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: xjjin@ybu.edu.cn.
Xuejun
X
Jin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D005663:Furans; D015870:Gene Expression / Q000187:drug effects*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D010957:Plasmids; D011809:Quinones; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005663:Furans; D016328:NF-kappa B; D010616:Phenanthrenes; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; C000713095:dihydrotanshinone I
Cancer; Dihydrotanshinone I; Inflammation; IκBα; Nuclear factor-κB (NF-κB)