p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells.
The biological activity of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investigated in human breast carcinoma (HBC) cells. Although capable of selective binding to the RAR gamma nuclear receptor, AHPN inhibited the growth of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP-1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibition of breast carcinoma growth and permit cell proliferation upon their removal, wher as AHPN induced G0/G1 arrest within 6h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G0/G1 arrest and apoptosis was accompanied by p53-independent regulation of WAF1/CIP1 as well as bax mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-mediated G0/G1 arrest and apoptosis was also associated with a concomitant up regulation of WAF1/CIP1 mRNA while these cells did not express bax or bcl-2 messages. Thus AHPN represents a novel retinoid that induces G0/G1 arrest and apoptosis via a unique pathway which appears to involve activation of known downstream effectors of p53 in a p53-independent manner.
Shao
Z M
ZM
Department of Medicine, University of Maryland Cancer Center, Baltimore, USA.
Dawson
M I
MI
Li
X S
XS
Rishi
A K
AK
Sheikh
M S
MS
Han
Q X
QX
Ordonez
J V
JV
Shroot
B
B
Fontana
J A
JA
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006131:Growth Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D009281:Naphthalenes / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C099555:CD 437; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006131:Growth Inhibitors; D009281:Naphthalenes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012176:Retinoids; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein