Roberson K M, Penland S N, Padilla G M, Selvan R S, Kim C S, Fine R L, Robertson C N
Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
Cell Growth Differ. 1997 Jan;8(1):101-11.
N-(4-Hydroxyphenyl)retinamide (4-HPR, Fenretinide) is a retinoid derivative with antineoplastic activity in various tumor types including prostate carcinoma. The mechanism of action of 4-HPR toxicity is unknown. 4-HPR induces apoptosis in leukemia- and lymphoma-derived cells, neuroblastoma, and small cell lung cancers. The present study was designed to investigate: (a) the mechanism of 4-HPR cytotoxicity in prostate cancer cells; and (b) correlate increased expression of transforming growth factor beta 1 (TGF beta 1) with induction of apoptosis. 4-HPR exposure to PC-3 cells in vitro was associated with apoptosis as evidenced by increased incidence of hypodiploid nuclei in propidium iodide fluorescence histograms and DNA fragmentation. An increase in the percentage of nuclei in the G1 phase of the cell cycle preceded induction of apoptosis. TGF beta 1-increased expression was noted in mRNA levels and in secretion of active TGF beta 1 into culture media. TGF beta 1 and TGF-beta receptor type II detected immunohistochemically were increased in 4-HPR-treated PC-3 cells. Furthermore, 4-HPR-induced cytotoxicity in PC-3 cells was abrogated by the addition of anti-TGF beta 1 antibody. In BT-20 cells, a 4-HPR-resistant breast carcinoma cell line, apoptosis was not observed after exposure to 4-HPR nor was TGF beta 1 expression enhanced in stained cells or in conditioned media. It is concluded that 4-HPR induces the expression of TGF beta 1 in association with the induction of apoptosis.
N-(4-羟基苯基)视黄酸酰胺（4-HPR，芬维A胺）是一种类维生素A衍生物，对包括前列腺癌在内的多种肿瘤类型具有抗肿瘤活性。4-HPR毒性的作用机制尚不清楚。4-HPR可诱导白血病和淋巴瘤来源的细胞、神经母细胞瘤及小细胞肺癌发生凋亡。本研究旨在探究：（a）4-HPR对前列腺癌细胞的细胞毒性机制；（b）转化生长因子β1（TGFβ1）表达增加与凋亡诱导之间的关联。体外将4-HPR作用于PC-3细胞可诱导凋亡，碘化丙啶荧光直方图中低二倍体细胞核发生率增加及DNA片段化可证明这一点。细胞周期G1期细胞核百分比增加先于凋亡诱导。在mRNA水平以及活性TGFβ1分泌至培养基中的过程中均发现TGFβ1表达增加。免疫组化检测发现，4-HPR处理的PC-3细胞中TGFβ1及II型TGF-β受体表达增加。此外，添加抗TGFβ1抗体可消除4-HPR对PC-3细胞的诱导细胞毒性作用。在BT-20细胞（一种对4-HPR耐药的乳腺癌细胞系）中，暴露于4-HPR后未观察到凋亡，染色细胞或条件培养基中的TGFβ1表达也未增强。研究得出结论，4-HPR诱导TGFβ1表达并伴随凋亡诱导。
