Acute cadmium exposure induces GSDME-mediated pyroptosis in triple-negative breast cancer cells through ROS generation and NLRP3 inflammasome pathway activation

Environ Toxicol Pharmacol. 2021 Oct:87:103686. doi: 10.1016/j.etap.2021.103686. Epub 2021 Jun 5.

Abstract

Cadmium (Cd) exposure can exert an impact on carcinogenicity of breast cancer, however, the mechanism is not fully understood in triple-negative breast cancer (TNBC). We performed a TNBC MDA-MB-231 cell model and assessed the toxic effect of Cd exposure (0, 10, 20, 50, 60, 80 μM). Cd reduced cell viability in a time- and dose-dependent manner, followed by cell cycle arrest in S phase with alterations of cyclin 1A1, cyclin 1D1 and CDK2. Lactate dehydrogenase (LDH) release, apoptosis and pyroptosis were increased, which were relieved by z-VAD. Elevated ROS and NLRP3, caspase-1, IL-1β and IL-18 were detected, which was attenuated by N-acetylcysteine. Increased bax and decreased caspase-8, caspase-9 and caspase-3 were found. gasdermin E (GSDME) was activated with cleavage of GSDME-NT, which was retarded by z-VAD. Additionally, p38 MAPK signaling pathway was activated. Our data demonstrate GSDME-activated pyroptosis in Cd toxicity, implying a potential impact on TNBC.

Keywords: Cadmium; GSDME; MDA-MB-231cells; NLRP3 inflammasome; Pyroptosis; ROS.

MeSH terms

  • Cadmium / toxicity*
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Inflammasomes / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Pyroptosis / drug effects
  • Reactive Oxygen Species / metabolism*
  • Receptors, Estrogen / metabolism*
  • Signal Transduction / drug effects
  • Triple Negative Breast Neoplasms / metabolism*

Substances

  • GSDME protein, human
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Reactive Oxygen Species
  • Receptors, Estrogen
  • Cadmium
  • CASP3 protein, human
  • Caspase 3