Lasiodin inhibits proliferation of human nasopharyngeal carcinoma cells by simultaneous modulation of the Apaf-1/caspase, AKT/MAPK and COX-2/NF-κB signaling pathways

PLoS One. 2014 May 20;9(5):e97799. doi: 10.1371/journal.pone.0097799. eCollection 2014.

Abstract

Rabdosia serra has been widely used for the treatment of the various human diseases. However, the antiproliferative effects and underlying mechanisms of the compounds in this herb remain largely unknown. In this study, an antiproliferative compound against human nasopharyngeal carcinoma (NPC) cells from Rabdosia serra was purified and identified as lasiodin (a diterpenoid). The treatment with lasiodin inhibited cell viability and migration. Lasiodin also mediated the cell morphology change and induced apoptosis in NPC cells. The treatment with lasiodin induced the Apaf-1 expression, triggered the cytochrome-C release, and stimulated the PARP, caspase-3 and caspase-9 cleavages, thereby activating the apoptotic pathways. The treatment with lasiodin also significantly inhibited the phosphorylations of the AKT, ERK1/2, p38 and JNK proteins. The pretreatment with the AKT or MAPK-selective inhibitors considerably blocked the lasiodin-mediated inhibition of cell proliferation. Moreover, the treatment with lasiodin inhibited the COX-2 expression, abrogated NF-κB binding to the COX-2 promoter, and promoted the NF-κB translocation from cell nuclei to cytosol. The pretreatment with a COX-2-selective inhibitor abrogated the lasiodin-induced inhibition of cell proliferation. These results indicated that lasiodin simultaneously activated the Apaf-1/caspase-dependent apoptotic pathways and suppressed the AKT/MAPK and COX-2/NF-κB signaling pathways. This study also suggested that lasiodin could be a promising natural compound for the prevention and treatment of NPC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptotic Protease-Activating Factor 1 / metabolism*
  • Carcinoma
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cyclooxygenase 2 / metabolism*
  • Cytochromes c / metabolism
  • Diterpenes, Kaurane / chemistry
  • Diterpenes, Kaurane / isolation & purification
  • Diterpenes, Kaurane / pharmacology*
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • Tracheophyta / chemistry

Substances

  • Antineoplastic Agents
  • Apoptotic Protease-Activating Factor 1
  • Diterpenes, Kaurane
  • NF-kappa B
  • lasiodin
  • Cytochromes c
  • Cyclooxygenase 2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Caspases

Grant support

The study is supported by the grants from the Science and Technology Planning Project of Guangdong Province in China (No. 2009B011300004), the National Natural Science Foundation of China (No. 31071638), the National Natural Science Foundation of China (No. 31101221/C200101) and Fundamental Research Funds for the Central Universities (Project No. 2014ZB0010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.