Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells

Yang Yang; Xiaolong Yan; Weixun Duan; Juanjuan Yan; Wei Yi; Zhenxin Liang; Ning Wang; Yue Li; Wensheng Chen; Shiqiang Yu; Zhenxiao Jin; Dinghua Yi

doi:10.1371/journal.pone.0062652

Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells

PLoS One. 2013 May 3;8(5):e62652. doi: 10.1371/journal.pone.0062652. Print 2013.

Authors

Yang Yang¹, Xiaolong Yan, Weixun Duan, Juanjuan Yan, Wei Yi, Zhenxin Liang, Ning Wang, Yue Li, Wensheng Chen, Shiqiang Yu, Zhenxiao Jin, Dinghua Yi

Affiliation

¹ Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an City, China.

Abstract

Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / metabolism
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Animals
Antineoplastic Agents / pharmacology*
Apoptosis
Cell Line, Tumor
Cell Shape
Cell Survival / drug effects
Dipeptides / pharmacology
Drug Resistance, Neoplasm
Drug Synergism
Glutathione / metabolism
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Nude
Proto-Oncogene Proteins c-akt / metabolism
Reactive Oxygen Species / metabolism
Receptor, Notch1 / antagonists & inhibitors
Receptor, Notch1 / genetics
Receptor, Notch1 / metabolism*
Signal Transduction
Stilbenes / pharmacology*
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Dipeptides
N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
NOTCH1 protein, human
Reactive Oxygen Species
Receptor, Notch1
Stilbenes
pterostilbene
Proto-Oncogene Proteins c-akt
Glutathione

Grants and funding

This study was supported by grants from the 12th National Five Years Supporting Project of China (2011BAI11B20), the National Natural Science Foundation of China (81102687 and 81070198), the Academic Promotion Project of Xijing Hospital (XJZT09 M16 and XJZT10 M12), and Social Development Project of Shaanxi Province (2012JQ4001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.