Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.
In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Willayat Yousuf
WY
Wani
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India; Radiation Oncology, Emory University, Atlanta, GA, USA; Garrison Institute on Aging, Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, TX, USA.
Ramesh J L
RJL
Kandimalla
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Deep Raj
DR
Sharma
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Alka
A
Kaushal
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Anand
A
Ruban
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Aditya
A
Sunkaria
Department of Physics, National Institute of Technology, Warangal, India.
Jayalakshmi
J
Vallamkondu
Department of Pre-clinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Alberto
A
Chiarugi
Garrison Institute on Aging, Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, TX, USA.
P Hemachandra
PH
Reddy
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Electronic address: kdgill2002@yahoo.co.in.
Kiran Dip
KD
Gill
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004006:Dichlorvos / Q000009:adverse effects* / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D062025:Organophosphate Poisoning / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats
D051017:Apoptosis Regulatory Proteins; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004006:Dichlorvos
Cyclin-D1; Dichlorvos; Neurodegeneration; Oxidative stress; p21