SP1-regulated p27/Kip1 gene expression is involved in terbinafine-induced human A431 cancer cell differentiation: An in vitro and in vivo study

Ching Shui Huang, Wei Lu Ho, Wen Sen Lee, Ming Thau Sheu, Ying Jan Wang, Shih Hsin Tu, Rong Jane Chen, Jan Show Chu, Li Ching Chen, Chia Hwa Lee, How Tseng, Yuan Soon Ho, Chih Hsiung Wu

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13 Citations (Scopus)

Abstract

In this study, the differentiation-promoting effects of terbinafine (Lamisil®, TB) were investigated in human epithelioid squamous carcinoma (A431) cells. The polyhydroxyethylmethacrylate (poly-HEMA)- and type-I collagen-coated culture plate models were adapted to harvest the TB-induced differentiated cells by agitation of the suspension medium. We demonstrated that p27/Kip1, p21/Cip1 and the keratinocyte differentiation marker, human involucrin (hINV), were induced (>25 μM) in TB-induced differentiated A431 cells. Animal studies demonstrated that administration of TB (10 mg/kg body weight) inhibited A431-xenografted tumor growth through differentiation processes as evidenced by expression of pancytokeratin in tumor tissues. Immunocytochemical staining analysis showed that p27/Kip1, but not p21/Cip1, positive-stained cells were detected in the early-differentiated cells of TB-treated tumor tissues. SP1, which regulates p27/Kip1 expression, was induced by TB (>10 μM) in A431 cells. The TB-induced promoter activity and protein expression levels of p27/Kip1 were significantly attenuated by pretreatment with mithramycin A, a SP1 specific inhibitor. We also demonstrated that TB-induced differentiated A431 cells sorted from the poly-HEMA-coated culture plates were arrested in the G1 phase. TB-induced G1 arrest in the suspension-cultured cells was attenuated by mithramycin A pretreatment. Such results suggest that SP1 plays a critical role in the p27/Kip1 gene transcriptional activation that may be subsequently involved in the TB-induced A431 cancer cell differentiation process.

Original languageEnglish
Pages (from-to)1783-1796
Number of pages14
JournalBiochemical Pharmacology
Volume75
Issue number9
DOIs
Publication statusPublished - 2008 May 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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