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Caspase-3 feedback loop enhances Bid-induced AIF/endoG and Bak activation in Bax and p53-independent manner

W Guo1, Y Zhang2, Z Ling3

  • 1Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, 17# People's South Road, Chengdu, Chengdu 610041, PR China.

Cell Death & Disease
|October 16, 2015
PubMed

Insights

Genistein induces cancer cell death independently of Bax or p53, offering a potential treatment for chemoresistance. This compound activates cell death pathways involving Bak, AIF, and endoG, even when Bax or p53 are deficient.

Area of Science:

  • * Molecular Biology
  • * Cancer Research
  • * Cell Death Mechanisms

Background:

  • * Chemoresistance in cancer is often linked to gene mutations or deficiencies, such as in Bax or p53.
  • * Existing cancer therapies face challenges when tumors develop resistance due to these genetic alterations.

Purpose of the Study:

  • * To identify an agent capable of overcoming chemoresistance caused by Bax or p53 deficiency.
  • * To elucidate the molecular mechanisms underlying genistein-induced cell death in cancer cells with deficient Bax or p53.

Main Methods:

  • * Utilized immunoblotting and flow-cytometry analysis to assess cell death.
  • * Employed gene interference techniques, including knockdown (KD) and knockout (KO) models (HCT116, DU145 cells).
  • * Investigated the roles of Bak, Apoptosis-Inducing Factor (AIF), and endonuclease G (endoG) in genistein-induced apoptosis.

Main Results:

  • * Genistein induced Bax/p53-independent apoptosis in cancer cells lacking Bax or p53 but expressing wild-type Bak.
  • * Bak knockdown only partially reduced genistein-induced apoptosis, indicating involvement of other pathways.
  • * Release of AIF and endoG contributed to cell death independently of Bak activation.
  • * A combination of AIF, endoG, and Bak knockdown almost completely abolished genistein-induced apoptosis.
  • * The Akt-Bid pathway mediated both Bak-dependent (caspase-dependent) and AIF/endoG-dependent (caspase-independent) cell death.
  • * Caspase-3 activation created a positive feedback loop, enhancing AIF/endoG release and Bak activation.

Conclusions:

  • * Genistein effectively induces cancer cell death through Bax/p53-independent mechanisms.
  • * Caspase-3 activation, via the Akt-Bid pathway, initiates genistein-induced apoptosis through a positive feedback loop.
  • * Genistein shows promise as a therapeutic agent for overcoming chemoresistance in cancers with dysfunctional Bax and p53 pathways.

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