PMID- 23431365
OWN - NLM
STAT- MEDLINE
DCOM- 20130815
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - Apigenin sensitizes prostate cancer cells to Apo2L/TRAIL by targeting adenine 
      nucleotide translocase-2.
PG  - e55922
LID - 10.1371/journal.pone.0055922 [doi]
LID - e55922
AB  - Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand 
      (TRAIL) is a promising cancer therapeutic agent. Recombinant human Apo2L/TRAIL 
      has been under clinical trials, whereas various kinds of malignant tumors have 
      resistance to Apo2L/TRAIL. We and others have shown that several anticancer 
      agents and flavonoids overcome resistance to Apo2L/TRAIL by upregulating death 
      receptor 5 (DR5) in malignant tumor cells. However, the mechanisms by which these 
      compounds induce DR5 expression remain unknown. Here we show that the dietary 
      flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), 
      resulting in enhancement of Apo2L/TRAIL-induced apoptosis by upregulation of DR5. 
      Apigenin and genistein, which are major flavonoids, enhanced Apo2L/TRAIL-induced 
      apoptosis in cancer cells. Apigenin induced DR5 expression, but genistein did 
      not. Using our method identifying the direct targets of flavonoids, we compared 
      the binding proteins of apigenin with those of genistein. We discovered that ANT2 
      was a target of apigenin, but not genistein. Similarly to apigenin, knockdown of 
      ANT2 enhanced Apo2L/TRAIL-induced apoptosis by upregulating DR5 expression at the 
      post-transcriptional level. Moreover, silencing of ANT2 attenuated the 
      enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest 
      that apigenin upregulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by 
      binding and inhibiting ANT2. We propose that ANT2 inhibitors may contribute to 
      Apo2L/TRAIL therapy.
FAU - Oishi, Masakatsu
AU  - Oishi M
AD  - Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical 
      Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, 
      Kamigyo-ku, Kyoto, Japan.
FAU - Iizumi, Yosuke
AU  - Iizumi Y
FAU - Taniguchi, Tomoyuki
AU  - Taniguchi T
FAU - Goi, Wakana
AU  - Goi W
FAU - Miki, Tsuneharu
AU  - Miki T
FAU - Sakai, Toshiyuki
AU  - Sakai T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130219
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adenine Nucleotide Translocator 2)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 7V515PI7F6 (Apigenin)
RN  - DH2M523P0H (Genistein)
SB  - IM
MH  - Adenine Nucleotide Translocator 2/antagonists & inhibitors/genetics/*metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - Apigenin/chemistry/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor/drug effects
MH  - Drug Synergism
MH  - Gene Knockdown Techniques
MH  - Genistein/chemistry
MH  - Humans
MH  - Male
MH  - Prostatic Neoplasms/*drug therapy
MH  - Protein Binding
MH  - RNA, Small Interfering/genetics
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/metabolism
MH  - TNF-Related Apoptosis-Inducing Ligand/*pharmacology
MH  - Up-Regulation/drug effects
PMC - PMC3576345
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/02/23 06:00
MHDA- 2013/08/16 06:00
PMCR- 2013/02/19
CRDT- 2013/02/23 06:00
PHST- 2012/10/09 00:00 [received]
PHST- 2013/01/03 00:00 [accepted]
PHST- 2013/02/23 06:00 [entrez]
PHST- 2013/02/23 06:00 [pubmed]
PHST- 2013/08/16 06:00 [medline]
PHST- 2013/02/19 00:00 [pmc-release]
AID - PONE-D-12-31040 [pii]
AID - 10.1371/journal.pone.0055922 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e55922. doi: 10.1371/journal.pone.0055922. Epub 2013 Feb 19.