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Nitrofen suppresses cell proliferation and promotes mitochondria-mediated apoptosis in type II pneumocytes
Qiang-Song Tong1, Li-Duan Zheng, Shao-Tao Tang
1Department of Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. qstong@mails.tjmu.edu.cn
Aim:
To characterize the molecular mechanisms of nitrofen-induced pulmonary hypoplasia.
Methods:
After administration of nitrofen to cultured type II A549 pneumocytes, cell proliferation and DNA synthesis were investigated by 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetry, colony formation assay, flow cytometry and [3H]-thymidine incorporation assay. Apoptosis was measured by terminal transferase-mediated dUTP nick-end-labeling, acridine orange-ethidium bromide staining and flow cytometry. Expression of proliferating cell nuclear antigen (PCNA) and apoptosis-related genes was assayed by immunofluorescence, RT-PCR and Western blot.
Results:
Nitrofen inhibited the cell proliferation of A549 cells in a dose- and time-dependent manner, accompanied by downregulation of PCNA. As a result, the DNA synthesis of nitrofentreated A549 cells decreased, while cell cycle was arrested at G0/G1 phase. Moreover, nitrofen induced apoptosis of A549 cells, which was not abolished by Z-Val-Ala- Asp(OCH3)- fluoromethylketone. In addition, nitrofen decreased the expression of Bcl-x( L), but not of Bcl-2, Bax, and Bak, resulting in a loss of mitochondrial membrane potential and the nuclear translocation of apoptosis-inducing factor (AIF). Meanwhile, nitrofen strongly activated the p38 mitogen-activated protein kinase (p38-MAPK). Pretreatment of cells with SB203580 (5 micromol/L) blocked nitrofen-induced phosphorylation of p38-MAPK and abolished nitrofen-induced AIF translocation and apoptosis in A549 cells.
Conclusion:
Nitrofen suppresses the proliferation of cultured type II pneumocytes accompanied by the downregulation of PCNA, and induces mitochondria-mediated apoptosis involving the activation of p38-MAPK.
Insights
Nitrofen inhibits lung cell proliferation and DNA synthesis by downregulating PCNA and arresting the cell cycle. It also triggers apoptosis via mitochondrial pathways involving p38-MAPK activation.
Area of Science:
- Molecular Biology
- Cell Biology
- Toxicology
Background:
- Pulmonary hypoplasia is a complex condition with poorly understood molecular underpinnings.
- Nitrofen is a known teratogen that can induce developmental abnormalities, including lung hypoplasia.
Purpose of the Study:
- To elucidate the molecular mechanisms by which nitrofen induces pulmonary hypoplasia.
- To investigate the effects of nitrofen on lung cell proliferation, DNA synthesis, and apoptosis.
Main Methods:
- Cultured type II A549 pneumocytes were treated with nitrofen.
- Cell proliferation, DNA synthesis, and apoptosis were assessed using various assays including MTT, colony formation, flow cytometry, and TUNEL.
- Expression of proliferating cell nuclear antigen (PCNA) and apoptosis-related genes (Bcl-2 family, AIF) was analyzed by immunofluorescence, RT-PCR, and Western blot. p38-MAPK activation was also investigated.
Main Results:
- Nitrofen inhibited A549 cell proliferation and DNA synthesis in a dose- and time-dependent manner, leading to G0/G1 cell cycle arrest and PCNA downregulation.
- Nitrofen induced apoptosis, characterized by loss of mitochondrial membrane potential and AIF translocation, independent of caspase pathways.
- Nitrofen-induced apoptosis was mediated by the activation of p38-MAPK, as demonstrated by the inhibitory effect of SB203580.
Conclusions:
- Nitrofen suppresses type II pneumocyte proliferation and DNA synthesis, associated with PCNA downregulation and cell cycle arrest.
- Nitrofen induces mitochondria-mediated apoptosis through p38-MAPK activation and AIF translocation.
- These findings provide insights into the molecular mechanisms of nitrofen-induced pulmonary hypoplasia.
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