N-(4-hydroxyphenyl)retinamide activation of transforming growth factor-beta and induction of apoptosis in human breast cancer cells.
N-(4 hydroxyphenyl)retinamide (4-HPR), a synthetic derivative of all-trans-retinoic acid, induces DNA synthesis arrest and apoptosis in human breast cancer cells in a dose- and time-dependent manner. MDA-MB-435 cells treated with 3 microM 4-HPR exhibited 58% and 75% DNA synthesis arrest after 1 and 2 days of treatment and 31%, 39%, 48%, and 56% apoptosis after 3, 4, 5, and 6 days of treatment, respectively. Conditioned media from 4-HPR-treated MDA-MB-435 cells contained 63 and 57 pg of active transforming growth factor-beta (TGF-beta) per 10(6) cells after 1 and 2 days of treatment, whereas conditioned media from control cells contained only 9 pg/10(6) cells. TGF-beta involvement in 4-HPR-induced apoptosis, but not DNA synthesis arrest, in MDA-MB-435 cells was demonstrated by 1) blockage of 4-HPR-induced apoptosis by 66-75% after treatment of cells with neutralizing antibodies to TGF-beta s, 2) blockage of 4-HPR-induced apoptosis by 64-67% after transient transfection of cells with antisense oligomers to TGF-beta 1 or TGF-beta type II receptor, 3) blockage of 4-HPR-induced apoptosis by approximately 50% after inhibition of latent TGF-beta activation, and 4) demonstration that human breast cancer cells (T47D) defective in TGF-beta signaling were refractive to 4-HPR-induced apoptosis. These data indicate that 4-HPR is a potent activator of TGF-beta and that TGF-beta participates in 4-HPR-induced apoptosis of human breast cancer cells.
Herbert
B S
BS
Department of Zoology, University of Texas at Austin 78712, USA.
Sanders
B G
BG
Kline
K
K
D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000937:Antigen-Antibody Reactions; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D017313:Fenretinide / Q000627:therapeutic use*; D006801:Humans; D008360:Mannosephosphates / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D000979:alpha-2-Antiplasmin / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D008360:Mannosephosphates; D016212:Transforming Growth Factor beta; D000979:alpha-2-Antiplasmin; D017313:Fenretinide; C027693:mannose-6-phosphate