PMID- 25980443
OWN - NLM
STAT- MEDLINE
DCOM- 20160520
LR  - 20181113
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 6
IP  - 19
DP  - 2015 Jul 10
TI  - Mitochondrial p53 phosphorylation induces Bak-mediated and caspase-independent 
      cell death.
PG  - 17192-205
AB  - Chemoresistance in cancer has previously been attributed to gene mutations or 
      deficiency. Caspase mutations or Bax deficiency can lead to resistance to cancer 
      drugs. We recently demonstrated that Bak initiates a caspase/Bax-independent cell 
      death pathway. We show that Plumbagin (PL) 
      (5-hydroxy-2-methyl-1,4-napthoquinone), a medicinal plant-derived naphthoquinone 
      that is known to have anti-tumor activity in a variety of models, induces 
      caspase-independent cell death in HCT116 Bax knockout (KO) or MCF-7 Bax knockdown 
      (KD) cells that express wild-type (WT) Bak. The re-expression of Bax in HCT116 
      Bax KO cells fails to enhance the PL-induced cell death. Additionally, Bak 
      knockdown by shRNA efficiently attenuates PL-induced cell death. These results 
      suggest that PL-induced cell death depends primarily on Bak, not Bax, in these 
      cells. Further experimentation demonstrated that p53 Ser15 phosphorylation and 
      mitochondrial translocation mediated Bak activation and subsequent cell death. 
      Knockdown of p53 or a p53 Ser15 mutant significantly inhibited p53 mitochondrial 
      translocation and cell death. Furthermore, we found that Akt mediated p53 
      phosphorylation and the subsequent mitochondrial accumulation. Taken together, 
      our data elaborate the role of Bak in caspase/Bax-independent cell death and 
      suggest that PL may be an effective agent for overcoming chemoresistance in 
      cancer cells with dysfunctional caspases.
FAU - Wang, Jinjing
AU  - Wang J
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Guo, Wenhao
AU  - Guo W
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Zhou, Hang
AU  - Zhou H
AD  - Department of Chemotherapy, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P. 
      R. China.
FAU - Luo, Na
AU  - Luo N
AD  - Nankai University School of Medicine, Collaborative Innovation Center of 
      Biotherapy, Tianjin 300071, P. R. China.
FAU - Nie, Chunlai
AU  - Nie C
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Zhao, Xinyu
AU  - Zhao X
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Yuan, Zhu
AU  - Yuan Z
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Liu, Xinyu
AU  - Liu X
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
FAU - Wei, Yuquan
AU  - Wei Y
AD  - Department of Abdominal Oncology, State Key Laboratory of Biotherapy and Cancer 
      Center, West China Hospital, Sichuan University and Collaborative Innovation 
      Center for Biotherapy, Chengdu 610041, P. R. China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (BAK1 protein, human)
RN  - 0 (Naphthoquinones)
RN  - 0 (RNA, Small Interfering)
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  - EC 3.4.22.- (Caspases)
RN  - YAS4TBQ4OQ (plumbagin)
SB  - IM
MH  - Antineoplastic Agents, Phytogenic/pharmacology
MH  - *Apoptosis/drug effects
MH  - Blotting, Western
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects/*physiology
MH  - Fluorescent Antibody Technique
MH  - Gene Knockdown Techniques
MH  - Gene Knockout Techniques
MH  - Humans
MH  - Mitochondria/metabolism
MH  - Naphthoquinones/pharmacology
MH  - Phosphorylation
MH  - RNA, Small Interfering
MH  - Transfection
MH  - Tumor Suppressor Protein p53/*metabolism
MH  - bcl-2 Homologous Antagonist-Killer Protein/*metabolism
MH  - bcl-2-Associated X Protein/metabolism
PMC - PMC4627301
OTO - NOTNLM
OT  - Akt
OT  - Bak
OT  - caspase-independent
OT  - p53
COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest.
EDAT- 2015/05/20 06:00
MHDA- 2016/05/21 06:00
PMCR- 2015/07/10
CRDT- 2015/05/19 06:00
PHST- 2015/01/19 00:00 [received]
PHST- 2015/04/10 00:00 [accepted]
PHST- 2015/05/19 06:00 [entrez]
PHST- 2015/05/20 06:00 [pubmed]
PHST- 2016/05/21 06:00 [medline]
PHST- 2015/07/10 00:00 [pmc-release]
AID - 3780 [pii]
AID - 10.18632/oncotarget.3780 [doi]
PST - ppublish
SO  - Oncotarget. 2015 Jul 10;6(19):17192-205. doi: 10.18632/oncotarget.3780.