PMID- 16024638
OWN - NLM
STAT- MEDLINE
DCOM- 20050914
LR  - 20191210
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 65
IP  - 14
DP  - 2005 Jul 15
TI  - Activation of nuclear factor-kappaB contributes to induction of death receptors 
      and apoptosis by the synthetic retinoid CD437 in DU145 human prostate cancer 
      cells.
PG  - 6354-63
AB  - Activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), 
      results in up-regulation of not only antiapoptotic genes but also proapoptotic 
      genes, including death receptor 4 (DR4) and death receptor 5 (DR5). Therefore, 
      NF-kappaB activation either suppresses or promotes apoptosis depending on the 
      type of stimulus or cell context. We showed previously that the synthetic 
      retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid 
      (CD437), effectively induces apoptosis particularly in androgen-independent 
      prostate carcinoma cells. This effect was associated with the ability of CD437 to 
      induce the expression of DR4 and DR5. In the present study, we examined the 
      hypothesis that NF-kappaB activation plays a role in CD437-induced death receptor 
      expression and apoptosis. Treatment of DU145 cells with CD437 resulted in a rapid 
      decrease (> or = 3 hours) of IkappaBalpha, which was accompanied by increased 
      translocation of the NF-kappaB subunit p65 from the cytoplasm to the nucleus and 
      increased NF-kappaB DNA-binding activity (> or = 4 hours). The NF-kappaB 
      inhibitor, helenalin, inhibited CD437-induced IkappaBalpha reduction and p65 
      nuclear translocation. Accordingly, it also abrogated CD437-induced up-regulation 
      of DR4, activation of caspase-8 and caspase-3, and increased DNA fragmentation. 
      Overexpression of an IkappaBalpha dominant-negative mutant blocked not only 
      CD437-induced p65 nuclear translocation but also DR4 up-regulation, caspase 
      activation, and DNA fragmentation. CD437 was unable to decrease IkappaBalpha 
      protein levels and up-regulate DR4 expression in CD437-resistant DU145 cells. 
      Moreover, knockdown of Fas-associated death domain, caspase-8, and DR4, 
      respectively, suppressed CD437-induced apoptosis. Collectively, these results 
      indicate that CD437 activates NF-kappaB via decreasing IkappaBalpha protein and 
      thereby induces DR4 expression and subsequent apoptosis in DU145 cells.
FAU - Jin, Fengshuo
AU  - Jin F
AD  - Department of Urology, Winship Cancer Institute, Emory University School of 
      Medicine, Atlanta, Georgia 30322, USA.
FAU - Liu, Xiangguo
AU  - Liu X
FAU - Zhou, Zhongmei
AU  - Zhou Z
FAU - Yue, Ping
AU  - Yue P
FAU - Lotan, Reuben
AU  - Lotan R
FAU - Khuri, Fadlo R
AU  - Khuri FR
FAU - Chung, Leland W K
AU  - Chung LW
FAU - Sun, Shi-Yong
AU  - Sun SY
LA  - eng
GR  - CA-098912/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (CD 437)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Retinoids)
RN  - 0 (Sesquiterpenes)
RN  - 0 (Sesquiterpenes, Guaiane)
RN  - 0 (TNFRSF10A protein, human)
RN  - 0 (TNFRSF10B protein, human)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - 4GUY9L896T (helenalin)
RN  - EC 3.4.22.- (CASP8 protein, human)
RN  - EC 3.4.22.- (Caspase 8)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Antineoplastic Agents, Phytogenic/pharmacology
MH  - Apoptosis/*drug effects/physiology
MH  - Caspase 8
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - I-kappa B Proteins/biosynthesis/metabolism
MH  - Male
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/antagonists & inhibitors/*metabolism
MH  - Prostatic Neoplasms/*drug therapy/metabolism/pathology
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand
MH  - Receptors, Tumor Necrosis Factor/*biosynthesis
MH  - Retinoids/*pharmacology
MH  - Sesquiterpenes/pharmacology
MH  - Sesquiterpenes, Guaiane
MH  - Up-Regulation/drug effects
EDAT- 2005/07/19 09:00
MHDA- 2005/09/15 09:00
CRDT- 2005/07/19 09:00
PHST- 2005/07/19 09:00 [pubmed]
PHST- 2005/09/15 09:00 [medline]
PHST- 2005/07/19 09:00 [entrez]
AID - 65/14/6354 [pii]
AID - 10.1158/0008-5472.CAN-04-4061 [doi]
PST - ppublish
SO  - Cancer Res. 2005 Jul 15;65(14):6354-63. doi: 10.1158/0008-5472.CAN-04-4061.