Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis.
Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis.
Research Wing, Bhopal Memorial Hospital and Research Centre, Bhopal, India; Department of Biotechnology, Dr. Hari Singh Gour Central University, Sagar, India.
Hariom
H
Panwar
Gorantla V
GV
Raghuram
Deepika
D
Jain
Alok K
AK
Ahirwar
Saba
S
Khan
Subodh K
SK
Jain
Neelam
N
Pathak
Smita
S
Banerjee
Kewal K
KK
Maudar
Pradyumna K
PK
Mishra
D000818:Animals; D063646:Carcinogenesis; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002869:Chromosome Aberrations / Q000139:chemically induced; D004249:DNA Damage; D004847:Epithelial Cells / Q000187:drug effects; D017953:Isocyanates / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D051379:Mice
D018797:Cell Cycle Proteins; D017953:Isocyanates; C008461:methyl isocyanate