Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells
Shumei Ma1, Xinxin Fu1, Lin Liu1
1School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
Frontiers in Cell and Developmental Biology
|November 1, 2021
Summary
Radiation therapy induces iron-dependent autophagic cell death in triple-negative breast cancer cells. Targeting iron metabolism may offer new therapeutic strategies for apoptosis-resistant breast cancers.
Area of Science:
- Oncology
- Cell Biology
- Radiotherapy
Background:
- Ionizing radiation is a cornerstone of cancer treatment, inducing cell death.
- The role of iron metabolism in radiation-induced cell death, particularly in breast cancer, remains incompletely understood.
- Different breast cancer subtypes exhibit varying responses to radiation, necessitating investigations into distinct cell death pathways.
Purpose of the Study:
- To investigate the mechanisms of radiation-induced cell death in breast cancer cells, focusing on the role of iron.
- To determine if iron accumulation influences specific cell death pathways like autophagy, apoptosis, ferroptosis, or necroptosis.
- To explore the potential of targeting iron metabolism for novel breast cancer therapeutic strategies.
Main Methods:
- Treatment of breast cancer cell lines (MDA-MB-231, BT549, MCF-7, zr-75) with ionizing radiation.
- Assessment of cell death induction using various inhibitors (deferoxamine, 3MA, Z-VAD-FMK, ferrostatin-1, Necrostatin-1) and gene silencing (ATG5, Beclin 1, transferrin).
- Analysis of iron accumulation, iron regulatory proteins (transferrin, CD71, Ferritin), lysosomal membrane permeabilization, cathepsin release, and reactive oxygen species (ROS) generation.
Main Results:
- Radiation-induced cell death varied among breast cancer cell lines, with autophagy prominent in MDA-MB-231 and BT549 cells.
- Iron chelator deferoxamine (DFO) and autophagy inhibition significantly reduced radiation-induced cell death in MDA-MB-231 cells, unlike apoptosis, ferroptosis, or necroptosis inhibitors.
- Radiation increased iron accumulation, transferrin, CD71, Ferritin, lysosomal iron release, and ROS generation, which were mitigated by DFO, N-acetylcysteine (NAC), and SOD2 overexpression, subsequently reducing autophagy and cell death.
Conclusions:
- Radiation-induced cell death in MDA-MB-231 breast cancer cells is iron-dependent and mediated by autophagy.
- Iron accumulation and subsequent ROS generation play a critical role in promoting radiation-induced autophagic cell death.
- These findings highlight iron metabolism as a potential therapeutic target for enhancing radiotherapy efficacy in apoptosis-resistant breast cancers.
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