Contribution of AP-1 Interference Induced by TAC-101 to Tumor Growth Suppression in a Hepatocellular Carcinoma Model

Abstract

TAC-101, 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid, is a synthetic ligand for retinoic acid receptor (RAR)-α. Here, we demonstrate the contribution of TAC-101-induced AP-1 interference to stabilization of tumor growth. TAC-101 induced transcriptional activation of RAR, resulting in marked elevation of RARβ, a representative retinoid response marker, and it also significantly repressed the transcriptional activity of AP-1 in JHH-7 cells. In contrast to JHH-7, JHH-6 is another RARα-expressing human hepatocellular carcinoma (HCC) cell line with constitutive activation of AP-1, but it is retinoid insensitive and did not respond to the TAC-101-induced RAR signal. TAC-101 did not inhibit AP-1 activity of the JHH-6 cell line, showing that AP-1 interference by TAC-101 must be in parallel with RAR activation. Interleukin-8 (IL-8), one of the AP-1-regulated factors which correlate with a poor prognosis in HCC patients, was found to be overexpressed in JHH-7 cells. TAC-101 reduced IL-8 production without cytotoxicity and inhibited the progression of HCC in the orthotopic mouse model with decreased tumor IL-8 level. These results suggest that downregulation of the extracellular biomarker for AP-1 interference via the induction of retinoid signals will enhance the pharmacological effect of TAC-101 on HCC and it could be useful as a surrogate biomarker of therapeutic efficacy.

Lack of association between FOS polymorphisms and clearance of HBV infection as well as HCC occurrence

“…A previous study has reported that the activity of AP-1 binding was increased by approximately 2.9-fold in the liver tumor compared with the nearby noncancerous tissue (Liu et al, 2002). In addition, it has been also suggested that AP-1 interferes with the suppression of tumor growth in HCC via the retinoid signals induced by 4-[3, 5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) (Eshima et al, 2009). Therefore, FOS, as a constituent of the transcription factor AP-1, might affect the signal transduction pathway of cell proliferation and apoptosis by pathological stimuli in human HCC (Guo et al, 2005).…”