Contribution of AP-1 interference induced by TAC-101 to tumor growth suppression in a hepatocellular carcinoma model.
TAC-101, 4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid, is a synthetic ligand for retinoic acid receptor (RAR)-alpha. 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 RARbeta, 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 RARalpha-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.
Eshima
Kokoro
K
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
Fukaya
Satoshi
S
Sugimoto
Akiko
A
Mori
Tomoko
T
Yokoi
Hiromi
H
Yamamoto
Yasuji
Y
Sugiura
Shin
S
Honda
Shizu
S
Masuko
Norio
N
Murakami
Koji
K
Yamasaki
Yasundo
Y
Kagechika
Hiroyuki
H
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008024:Ligands; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014297:Trimethylsilyl Compounds / Q000494:pharmacology*
D001565:Benzoates; D014408:Biomarkers, Tumor; D016209:Interleukin-8; D008024:Ligands; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C112689:TAC 101; D018808:Transcription Factor AP-1; D014297:Trimethylsilyl Compounds; C082925:retinoic acid receptor beta