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Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis

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Title Bak Compensated for Bax in p53-null Cells to Release
Cytochrome c for the Initiation of Mitochondrial
Signaling during Withanolide D-Induced Apoptosis
 
Creator Mondal, Susmita
Bhattacharya, Kaushik
Mallick, Asish
Sangwan, Rajender
Mandal, Chitra
 
Subject Infectious Diseases and Immunology
 
Description The goal of cancer chemotherapy to induce multi-directional apoptosis as targeting a single pathway is unable to decrease
all the downstream effect arises from crosstalk. Present study reports that Withanolide D (WithaD), a steroidal lactone
isolated from Withania somnifera, induced cellular apoptosis in which mitochondria and p53 were intricately involved. In
MOLT-3 and HCT116p53+/+ cells, WithaD induced crosstalk between intrinsic and extrinsic signaling through Bid, whereas
in K562 and HCT116p532/2 cells, only intrinsic pathway was activated where Bid remain unaltered. WithaD showed
pronounced activation of p53 in cancer cells. Moreover, lowered apoptogenic effect of HCT116p532/2 over HCT116p53+/+
established a strong correlation between WithaD-mediated apoptosis and p53. WithaD induced Bax and Bak upregulation
in HCT116p53+/+, whereas increase only Bak expression in HCT116p532/2 cells, which was coordinated with augmented
p53 expression. p53 inhibition substantially reduced Bax level and failed to inhibit Bak upregulation in HCT116p53+/+ cells
confirming p53-dependent Bax and p53-independent Bak activation. Additionally, in HCT116p53+/+ cells, combined loss of
Bax and Bak (HCT116Bax2Bak2) reduced WithaD-induced apoptosis and completely blocked cytochrome c release
whereas single loss of Bax or Bak (HCT116Bax2Bak+/HCT116Bax+Bak2) was only marginally effective after WithaD
treatment. In HCT116p532/2 cells, though Bax translocation to mitochondria was abrogated, Bak oligomerization helped
the cells to release cytochrome c even before the disruption of mitochondrial membrane potential. WithaD also showed in
vitro growth-inhibitory activity against an array of p53 wild type and null cancer cells and K562 xenograft in vivo. Taken
together, WithaD elicited apoptosis in malignant cells through Bax/Bak dependent pathway in p53-wild type cells, whereas
Bak compensated against loss of Bax in p53-null cells.
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1541/1/PLOS_ONE__7(_3);2012[38].pdf
Mondal, Susmita and Bhattacharya, Kaushik and Mallick, Asish and Sangwan, Rajender and Mandal, Chitra (2012) Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis. PLoS ONE , 7 (3). e34277.
 
Relation http://dx.doi.org/10.1371/journal.pone.0034277
http://www.eprints.iicb.res.in/1541/