Mitochondria‐mediated caspase‐independent apoptosis induced by cadmium in normal human lung cells

Abstract

Cadmium, a well-known environmental hazard, has caused serious health problems in humans and animals. Accumulating evidence suggests the cadmium toxicity is mediated by oxidative stress-induced cell death. However, the molecular signaling underlying cadmium-induced apoptosis remains unclear. In this study, we demonstrate here that cadmium induced mixed types of cell death including primary apoptosis (early apoptosis), secondary necrosis (late apoptosis), and necrosis in normal human lung cells, MRC-5, as revealed by chromatin condensation, phosphatidylserine (PS) externalization, and hypodiploid DNA content. The total apoptotic cells reached a plateau of around 40.0% after 24 h exposure of 100 microM cadmium. Pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum of caspase inhibitor, could not rescue apoptotic cells from cadmium toxicity. Coincidently, we failed to detect the activation of pro-caspase-3 and cleavage of PARP by immunoblot, which implies the apoptogenic activity of cadmium in MRC-5 cells is caspase-independent. JC-1 staining also indicated that mitochondrial depolarization is a prelude to cadmium-induced apoptosis, which was accompanied by a translocation of caspase-independent pro-apoptotic factor apoptosis-inducing factor (AIF) into the nucleus as revealed by the immunofluorescence assay. In summary, this study demonstrated for the first time that cadmium induced a caspase-independent apoptotic pathway through mitochondria-mediated AIF translocation into the nucleus.

Cadmium Renal Toxicity <i>via</i> Apoptotic Pathways

“…5,6) Apoptosis disorders induce a disruption of tissue homeostasis and functions and are associated with many diseases, such as cancer, neurodegenerative disease and toxin-induced disease. 7) Cadmium can induce apoptosis in various tissues and cultured cells, including mouse liver, 8) rat kidney and testis, [9][10][11][12][13] human T cell line (CEM-C12 cells), lymphoma U937 cells, normal hepatocytes, liver L-02 cells, fetal lung fibroblast MRC-5 cells and prostate epithelial cells, [14][15][16][17][18][19] mouse mesangial cells, 20) rat lung epithelial cells, cortical neurons and renal tubular epithelial cells, [21][22][23] and porcine kidney LLC-PK 1 cells. 24) These observations indicate that cell death of the proximal tubule cells in the kidney through apoptotic pathways is one of the key events in cadmium-induced renal toxicity.…”

LRG-accelerated differentiation defines unique G-CSFR signaling pathways downstream of PU.1 and C/EBPε that modulate neutrophil activation

“…Whole cell lysates (WCL) from unstimulated and differentiated cells were prepared as described [15]. Protein concentrations were determined using a BCA kit (Rockford, IL).…”

Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells

“…However, there have also been reports of Cd 2ϩ -induced caspase-independent cell death. For example, in Cd 2ϩ -treated MRC-5 cells, apoptosis-like nuclear changes were mediated by AIF (41).…”