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




Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis - Download this document for free, or read online. Document in PDF available to download.

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 HCT116p53−-− cells, only intrinsic pathway was activated where Bid remain unaltered. WithaD showed pronounced activation of p53 in cancer cells. Moreover, lowered apoptogenic effect of HCT116p53−-− 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 HCT116p53−-− 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 HCT116Bax−Bak− reduced WithaD-induced apoptosis and completely blocked cytochrome c release whereas single loss of Bax or Bak HCT116Bax−Bak+-HCT116Bax+Bak− was only marginally effective after WithaD treatment. In HCT116p53−-− 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.



Author: Susmita Mondal, Kaushik Bhattacharya, Asish Mallick, Rajender Sangwan, Chitra Mandal

Source: http://plos.srce.hr/



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