Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines.
6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN or CD437), originally identified as a retinoic acid receptor gamma-selective retinoid, was previously shown to induce growth inhibition and apoptosis in human breast cancer cells. In this study, we investigated the role of AHPN/CD437 and its mechanism of action in human lung cancer cell lines. Our results demonstrated that AHPN/CD437 effectively inhibited lung cancer cell growth by inducing G0/G1 arrest and apoptosis, a process that is accompanied by rapid induction of c-Jun, nur77, and p21(WAF1/CIP1). In addition, we found that expression of p53 and Bcl-2 was differentially regulated by AHPN/CD437 in different lung cancer cell lines and may play a role in regulating AHPN/CD437-induced apoptotic process. On constitutive expression of the c-JunAla(63,73) protein, a dominant-negative inhibitor of c-Jun, in A549 cells, nur77 expression and apoptosis induction by AHPN/CD437 were impaired, whereas p21(WAF1/CIP1) induction and G0/G1 arrest were not affected. Furthermore, overexpression of antisense nur77 RNA in A549 and H460 lung cancer cell lines largely inhibited AHPN/CD437-induced apoptosis. Thus, expression of c-Jun and nur77 plays a critical role in AHPN/CD437-induced apoptosis. Together, our results reveal a novel pathway for retinoid-induced apoptosis and suggest that AHPN/CD437 or analogs may have a better therapeutic efficacy against lung cancer.
Li
Y
Y
The Burnham Institute, Cancer Research Center, La Jolla, California 92037, USA.
Lin
B
B
Agadir
A
A
Liu
R
R
Dawson
M I
MI
Reed
J C
JC
Fontana
J A
JA
Bost
F
F
Hobbs
P D
PD
Zheng
Y
Y
Chen
G Q
GQ
Shroot
B
B
Mercola
D
D
Zhang
X K
XK
D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D016193:G1 Phase; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D016192:Resting Phase, Cell Cycle; D012176:Retinoids / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
C099555:CD 437; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016755:Proto-Oncogene Proteins c-jun; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012176:Retinoids; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014212:Tretinoin