Cell death induced by N-(4-hydroxyphenyl)retinamide in human epidermal keratinocytes is modulated by TGF-β and diminishes during the progression of squamous cell carcinoma
✍ Scribed by Maria Davies; Ian C. Paterson; Anu Ganapathy; Stephen S. Prime
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- French
- Weight
- 479 KB
- Volume
- 119
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
It has been demonstrated that the chemopreventive agent N‐(4‐hydroxyphenyl)retinamide (4‐HPR) induces apoptotic cell death, but recent data has suggested that late stage/recurrent tumours lose their response to 4‐HPR‐induced cell death by mechanisms that are unknown. Our study investigated the ability of 4‐HPR to induce cell death in keratinocyte cell lines that represent different stages of carcinogenesis and the role of TGF‐β signalling in the induction of cell death by 4‐HPR. We show that treatment of the immortalised keratinocyte cell line HaCaT with 10^−5^ M 4‐HPR induced cell death by apoptosis and caused an accumulation of cells in the G0/G1 phase of the cell cycle. Using a genetically related series of human skin keratinocytes derived from HaCaT that reflect tumour progression and metastasis in vivo, we demonstrate that 4‐HPR‐induced cell death and apoptosis is attenuated in the more aggressive tumour cell lines but that a reduced level of response is retained. Response to TGF‐β‐induced growth inhibition was also reduced in the more aggressive cell lines. Treatment of HaCaT cells with 4‐HPR induced TGF‐β2 expression and an increase in the amount of active TGF‐β in the culture medium. The inhibition of TGF‐β signalling attenuated 4‐HPR‐induced apoptosis and both TGF‐β1 and TGF‐β2 potentiated 4‐HPR‐induced apoptosis and enhanced 4‐HPR‐induced growth inhibition. Our results demonstrate that loss of response to 4‐HPR correlates with a loss of response to the growth inhibitory effects of TGF‐β and that adjuvant therapies that upregulate TGF‐β may enhance the chemopreventive effects of 4‐HPR. © 2006 Wiley‐Liss, Inc.