# Niclosamide-Modulated Apoptosis and Autophagy in Breast Cancer Cells via Phosphorylated JNK as a Common Regulator

## TL;DR

Niclosamide induces cell death in breast cancer cells by regulating autophagy and apoptosis, with phosphorylated JNK acting as a key regulator.

## Contribution

Phosphorylated JNK is identified as a novel common regulator of niclosamide-induced autophagy and apoptosis.

## Key findings

- Niclosamide induces G0/G1 cell cycle arrest and apoptosis in MCF-7 and T-47D breast cancer cells.
- Phosphorylated JNK regulates niclosamide-induced autophagy and apoptosis via ROS-dependent or ROS-independent pathways.
- Blocking autophagy enhances niclosamide-induced apoptosis in breast cancer cells.

## Abstract

Autophagy plays critical pro-survival and pro-apoptotic roles in regulating breast cancer death. Niclosamide is a U.S. FDA-approved drug that is used for parasite treatment. Exposure to niclosamide causes apoptosis in several different types of cancer cells, whereas its ability to regulate autophagy remains limited, especially in breast cancer. In this study, we evaluated the relative mechanism by which niclosamide regulates apoptosis and autophagy in breast cancer cells. We found that niclosamide induced G0/G1 cell cycle arrest and apoptosis in MCF-7 and T-47D cells. It also caused the turnover of microtubule-associated protein 1 light chain 3 (LC3-II), an autophagy marker, and arrested autophagosome maturation. Niclosamide-induced apoptosis was inhibited by an autophagy initiator (3-methyladenine) but significantly enhanced by chloroquine, an autophagy blocker. Both Jun-amino-terminal kinase (JNK) and reactive oxygen species (ROS) inhibitors decreased LC3-II accumulation and niclosamide-induced apoptosis. However, the ROS inhibitor reduced the expression of niclosamide-activated p-JNK in MCF-7 cells but not in T-47D cells. In conclusion, blocking autophagy is cytotoxic and promotes niclosamide-induced apoptosis. Phosphorylated JNK is identified for the first time as a common regulator of niclosamide-induced autophagy and apoptosis, acting through ROS-dependent or ROS-independent pathways.