Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway.

Abstract

Ampelopsin (AMP), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. In this study, we investigated its anti-cancer activity in human breast cancer cell lines, and explored the underlying mechanism of this action. Our results showed that treatment with AMP dose-dependently inhibited cell viability and induced apoptosis in MCF-7 and MDA-MB-231 breast cancer cells without cytotoxicity in human normal breast epithelial cells MCF-10A. Meanwhile, AMP dose- dependently triggered reactive oxygen species (ROS) generation in both breast cancer cells. The ROS scavenger N-acetyl-L-cysteine (NAC) strongly attenuated AMP-induced ROS production, along with cell growth inhibition and apoptosis. Furthermore, AMP was observed to activate endoplasmic reticulum (ER) stress, as evidenced by the up-regulation of ER stress-related proteins, including GRP78, p-PERK, p-elF2α, cleaved ATF6α and CHOP, while knockdown of ATF6α or PERK markedly down-regulated AMP-induced CHOP expression. Blocking ER stress using 4-phenylbutyric acid not only down-regulated AMP-induced GRP78 and CHOP expression, but also significantly decreased AMP-induced cell growth inhibition and apoptosis, whereas ER stress inducer thapsigargin played opposing effects. Additionally, NAC inhibited AMP-induced ER stress by down-regulating GRP78 and CHOP expression. Conversely, blocking ER stress using CHOP siRNA decreased AMP-induced ROS production and cell apoptosis. Taken together, these results demonstrate that AMP has anti-tumor effects against breast cancer cells through ROS generation and ER stress pathway, which therefore provide experimental evidences for developing AMP as a new therapeutic drug for breast cancer.

• Authors: Yong Zhou, Furong Shu, Xinyu Liang, Hui Chang, Linying Shi, Xiaoli Peng, Jundong Zhu, Mantian Mi
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e89021 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24551210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• Antineoplastic Agents, Phytogenic
• DDIT3 protein, human
• Endoplasmic Reticulum Chaperone BiP
• Flavonoids
• HSPA5 protein, human
• Heat-Shock Proteins
• Phenylbutyrates
• RNA, Small Interfering
• Reactive Oxygen Species
• Transcription Factors
• Transcription Factor CHOP
• ELF2 protein, human
• ampelopsin
• Thapsigargin
• 4-phenylbutyric acid
• EIF2AK3 protein, human
• eIF-2 Kinase
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Activating Transcription Factor 6 (genetics, metabolism)
• Ampelopsis (chemistry)
• Antineoplastic Agents, Phytogenic (isolation & purification, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects, genetics)
• Female
• Flavonoids (isolation & purification, pharmacology)
• Gene Expression Regulation, Neoplastic
• Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• Humans
• Phenylbutyrates (pharmacology)
• RNA, Small Interfering (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Thapsigargin (pharmacology)
• Transcription Factor CHOP (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• eIF-2 Kinase (genetics, metabolism)