Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis.
The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN, CD437) induces apoptosis in a variety of cell types, many of which are cancer cells that resist the antiproliferative and/or differentiating effects of retinoids. While the retinoids exert their effects by binding to the retinoic acid nuclear receptors (RARs) or retinoid X receptors (RXRs), AHPN (CD437) binds to another protein with different ligand specificity. In nuclear extracts from HL-60R cells the binding of AHPN (CD437) was only minimally competed by either retinoic acid (tRA)or 9-cis-retinoic acid (9-cis-RA), the natural ligands for the RARs and RXRs, respectively. Moreover, AHPN (CD437) was unable to compete with either tRA or 9-cis-RA for binding to endogenous retinoid receptors in nuclear extracts from the MDA-MB-468 breast carcinoma cell line. Size exclusion chromatography revealed AHPN binding to a 95 kDa protein(s) which is neither an RAR or RXR. Our results suggest that apoptosis induction by AHPN (CD437) may occur through interaction with another protein and is independent of the RAR/RXR-signaling pathways.
Fontana
J A
JA
Department of Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA. Joseph.Fontana@med.va.gov
Dawson
M I
MI
Leid
M
M
Rishi
A K
AK
Zhang
Y
Y
Hsu
C A
CA
Lu
J S
JS
Peterson
V J
VJ
Jong
L
L
Hobbs
P
P
Chao
W R
WR
Shroot
B
B
Reichert
U
U
D000970:Antineoplastic Agents / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism; D002352:Carrier Proteins / Q000302:isolation & purification* / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism* / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D000097768:Retinoic Acid Receptor gamma; C099555:CD 437