Ferritinophagy-Mediated Ferroptosis and Activation of Keap1/Nrf2/HO-1 Pathway Were Conducive to EMT Inhibition of Gastric Cancer Cells in Action of 2,2'-Di-pyridineketone Hydrazone Dithiocarbamate Butyric Acid Ester.

Deng Guan,Chunjie Yang,Yun Fu,Ruifang Xu,Kangwei Zheng,Changzheng Li,Wei Zhou,Yongli Li,Rui Feng,Ting Wang,Huiping Wei,Cuiping Li,Milena Georgieva

doi:10.1155/2022/3920664

Abstract

In metastasis of cancer cells, the epithelial-mesenchymal transition (EMT) is prerequired. Ferroptosis is an iron-mediated cellular death process, but whether it involves EMT regulation remains elusive. In addition, how stress responders (Nrf2) respond to the redox alteration and cross-talking between them needs to be determined. Our data revealed that DpdtbA (2,2′-di-pyridineketone hydrazone dithiocarbamate butyric acid ester) resisted TGF-β1-induced EMT in gastric cancer lines (SGC-7901 and MGC-823) through ferritinophagy-mediated ROS production. Furthermore, the depletion of Gpx4 and xCT as well as enhanced lipid peroxidation indicated that DpdtbA acted as Erastin did in ferroptosis induction, which thus provided chance to explore the causal relationship between ferroptosis and EMT. Our data illustrated that ferritinophagy-mediated ferroptosis promoted the EMT inhibition. In addition, activated Nrf2 involved the regulation on both ferroptosis and EMT in response to the alteration in the cellular redox environment. In brief, ferritinophagy-mediated ferroptosis and activation of the Keap1/Nrf2/HO-1 pathway were conducive to the EMT inhibition.

Highlights

The uncontrollable propagation and migration to the nearby organs are one of the features of cancerous cells [1], while the undergoing epithelial-mesenchymal transition (EMT) is a prerequisite
We found that di-pyridylketone hydrazone dithiocarbamate butyric acid (DpdtbA) treatment resulted in depletion of glutathione peroxidase 4 (Gpx4) and xCT and increase in lipid peroxidation, hinting there was an occurrence of ferroptosis; the causal relationship between EMT and ferroptosis was explored
The EMTrelated proteins were faded in red fluorescence and enhanced in green (E-cadherin) even in the presence of transforming growth factor (TGF)-β1

Summary

Introduction

The uncontrollable propagation and migration to the nearby organs are one of the features of cancerous cells [1], while the undergoing epithelial-mesenchymal transition (EMT) is a prerequisite. During EMT, the tumor cells lose cell-cell adhesion and gain the traits of migration and invasion. The transforming growth factor (TGF), cytokine, nuclear receptor, receptor tyrosine kinase (RTK), and reactive oxygen species (ROS) are shown to play a role in the EMT regulation [5,6,7]. In addition to the abovementioned, EMT is in a hybrid E/M phenotype for cancer cells, and “phenotypic stability factors” (PSFs, GRHL2, OVOL2, ΔNp63α, and NUMB) can maintain the hybrid E/M phenotype [8,9,10,11], indicating that the EMT process is quite complex. EMT enables the multistep process leading to the colonization of distant anatomical sites and endows malignant cells with an accrued resistance to a variety of therapeutic regimens [12]

Methods

Results

Conclusion