title: Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway.
abstract: Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies.
authors: Department of Biochemistry and Molecular Biology, College of Basic Medical Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. lvcuiting961021@126.com
authors: Cuiting
authors: C
authors: Lv
authors: Wenxia
authors: W
authors: Sun
authors: Haofen
authors: H
authors: Sun
authors: Shanjian
authors: S
authors: Wei
authors: Ruohua
authors: R
authors: Chen
authors: Bingui
authors: B
authors: Wang
authors: Caiguo
authors: C
authors: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents; D008175:Lung Neoplasms / Q000188:drug therapy; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004224:Diterpenes; D007166:Immunosuppressive Agents; C087628:TCEAL1 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C571435:asperolide A; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins; D002945:Cisplatin