PMID- 26469967 OWN - NLM STAT- MEDLINE DCOM- 20160621 LR - 20220331 IS - 2041-4889 (Electronic) VI - 6 IP - 10 DP - 2015 Oct 15 TI - Caspase-3 feedback loop enhances Bid-induced AIF/endoG and Bak activation in Bax and p53-independent manner. PG - e1919 LID - 10.1038/cddis.2015.276 [doi] AB - Chemoresistance in cancer has previously been attributed to gene mutations or deficiencies. Bax or p53 deficiency can lead to resistance to cancer drugs. We aimed to find an agent to overcome chemoresistance induced by Bax or p53 deficiency. Here, we used immunoblot, flow-cytometry analysis, gene interference, etc. to show that genistein, a major component of isoflavone that is known to have anti-tumor activities in a variety of models, induces Bax/p53-independent cell death in HCT116 Bax knockout (KO), HCT116 p53 KO, DU145 Bax KO, or DU145 p53 KO cells that express wild-type (WT) Bak. Bak knockdown (KD) only partially attenuated genistein-induced apoptosis. Further results indicated that the release of AIF and endoG also contributes to genistein-induced cell death, which is independent of Bak activation. Conversely, AIF and endoG knockdown had little effect on Bak activation. Knockdown of either AIF or endoG alone could not efficiently inhibit apoptosis in cells treated with genistein, whereas an AIF, endoG, and Bak triple knockdown almost completely attenuated apoptosis. Next, we found that the Akt-Bid pathway mediates Bak-induced caspase-dependent and AIF- and endoG-induced caspase-independent cell death. Moreover, downstream caspase-3 could enhance the release of AIF and endoG as well as Bak activation via a positive feedback loop. Taken together, our data elaborate the detailed mechanisms of genistein in Bax/p53-independent apoptosis and indicate that caspase-3-enhanced Bid activation initiates the cell death pathway. Our results also suggest that genistein may be an effective agent for overcoming chemoresistance in cancers with dysfunctional Bax and p53. FAU - Guo, W AU - Guo W AD - Department 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. FAU - Zhang, Y AU - Zhang Y AD - Departmant of Oncology, Guizhou People's Hospital, Guizhou 550002, PR China. FAU - Ling, Z AU - Ling Z AD - Departmant of Oncology, The Fourth People's Hospital of Sichuan province, Chengdu 610041, PR China. FAU - Liu, X AU - Liu X AD - Department 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. FAU - Zhao, X AU - Zhao X AD - Department 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. FAU - Yuan, Z AU - Yuan Z AD - Department 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. FAU - Nie, C AU - Nie C AD - Department 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. FAU - Wei, Y AU - Wei Y AD - Department 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151015 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (AIFM1 protein, human) RN - 0 (Apoptosis Inducing Factor) RN - 0 (BAK1 protein, human) RN - 0 (BAX protein, human) RN - 0 (BH3 Interacting Domain Death Agonist Protein) RN - 0 (BID protein, human) RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (bcl-2 Homologous Antagonist-Killer Protein) RN - 0 (bcl-2-Associated X Protein) RN - DH2M523P0H (Genistein) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.- (Endodeoxyribonucleases) RN - EC 3.1.21.- (endonuclease G) RN - EC 3.4.22.- (CASP3 protein, human) RN - EC 3.4.22.- (Caspase 3) SB - IM MH - Apoptosis/drug effects MH - Apoptosis Inducing Factor/*metabolism MH - BH3 Interacting Domain Death Agonist Protein/*physiology MH - Caspase 3/*physiology MH - Cell Line, Tumor MH - Endodeoxyribonucleases/*physiology MH - Feedback, Physiological MH - Genistein/pharmacology MH - Humans MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction MH - Tumor Suppressor Protein p53/*metabolism MH - bcl-2 Homologous Antagonist-Killer Protein/*metabolism MH - bcl-2-Associated X Protein/*metabolism PMC - PMC4632302 EDAT- 2015/10/16 06:00 MHDA- 2016/06/22 06:00 PMCR- 2015/10/01 CRDT- 2015/10/16 06:00 PHST- 2015/04/29 00:00 [received] PHST- 2015/07/21 00:00 [revised] PHST- 2015/08/28 00:00 [accepted] PHST- 2015/10/16 06:00 [entrez] PHST- 2015/10/16 06:00 [pubmed] PHST- 2016/06/22 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - cddis2015276 [pii] AID - 10.1038/cddis.2015.276 [doi] PST - epublish SO - Cell Death Dis. 2015 Oct 15;6(10):e1919. doi: 10.1038/cddis.2015.276.