Combination of pristimerin and paclitaxel additively induces autophagy in human breast cancer cells via ERK1/2 regulation.

Abstract

Pristimerin, a quinonemethide triterpenoid, has demonstrated anticancer activity against a number of types of cancer, including breast cancer. However, its mechanism of action remains unclear. The present study investigated the autophagy‑induced anticancer efficacy of pristimerin on MDA‑MB‑231 human breast cancer cells. Pristimerin inhibited the growth of these cells in a concentration‑dependent manner. Treatment with pristimerin dose‑dependently induced an increase of light chain 3B (LC3‑II), whereas autophagy inhibitor 3‑methyladenine (3‑MA) inhibited pristimerin‑induced LC3‑II accumulation and cytotoxic effects. Autophagy was also activated by paclitaxel as observed by an elevated LC3‑II level. Although 24 µM paclitaxel induced autophagy without cytotoxicity, combined with pristimerin it additively induced cell growth inhibition and autophagy induction. Autophagy induction was measured with an autophagy detection kit and LC3‑II levels were monitored by western blot analysis. Treatment with 3‑MA inhibited LC3‑II accumulation and cell death induced by a combination of paclitaxel and pristimerin. Pristimerin and paclitaxel inhibited extracellular signal‑regulated kinase (ERK)1/2/p90RSK signaling, consistent with autophagy indicators, namely p62 degradation and beclin 1 expression. In addition, ERK activator ceramide C6 treatment suppressed the LC3‑II levels induced by a combination of paclitaxel and pristimerin. These results suggested that exposure to pristimerin induced autophagic cell death, whereas a combination treatment of pristimerin and paclitaxel resulted in an additive effect on ERK‑dependent autophagic cell death.

• Authors: Younju Lee, Jinuk Na, Myung Sun Lee, Eun Young Cha, Ji Young Sul, Jun Beom Park, Jin Sun Lee
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 18 Issue 5 Pg. 4281-4288 (Nov 2018) ISSN: 1791-3004 [Electronic] Greece
• PMID: 30221728 (Publication Type: Journal Article)

Chemical References

• Pentacyclic Triterpenes
• Triterpenes
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• celastrol
• Paclitaxel

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Female
• Humans
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Paclitaxel (pharmacology)
• Pentacyclic Triterpenes
• Triterpenes (pharmacology)