Japanese Journal of Clinical Oncology 31:359-362 (2001)
© 2001 Foundation for Promotion of Cancer Research
Apoptosis Induction by Acyclic Retinoid: a Molecular Basis of ‘Clonal Deletion’ Therapy for Hepatocellular Carcinoma
1First Department of Internal Medicine and 2Department of Molecular Pathobiochemistry, Gifu University School of Medicine, Gifu and 3Laboratory of Molecular Cell Sciences, Tsukuba Institute, The RIKEN, Tsukuba, Ibaraki, Japan
We have shown previously that administration of acyclic retinoid to cirrhotic patients who had undergone curative treatment of preceding hepatocellular carcinoma (HCC) induced the disappearance of serum lectin-reactive 
-fetoprotein (AFP-L3) and subsequently reduced the incidence of second liver cancers. AFP-L3 is a tumor marker that indicates the presence of occult tumors below the detection limit by diagnostic images. Therefore, we have proposed a new concept of ‘clonal deletion’ therapy with acyclic retinoid for the cancer chemoprevention against HCC. Such eradication of AFP-L3-producing latent malignant (or premalignant) cells from the liver suggested a new strategy to prevent HCC, which may be involved in the same category as cancer chemotherapy. In the present series of studies, we explored the molecular mechanism of ‘clonal deletion’ and found a novel mechanism of apoptosis induction by the retinoid. We have demonstrated a modification of a retinoid receptor, RXR, by mitogen-activated protein (MAP) kinase-dependent phosphorylation, resulting in the loss of transactivating activity. This may lead HCC cells to be resistant to natural retinoic acid. However, acyclic retinoid restored the function of phosphorylated RXR and induced its downstream pro-apoptotic genes including tissue transglutaminase, an enzyme that is implicated in apoptosis. Tissue transglutaminase-dependent apoptosis in HCC cells was independent of the activation of caspases. This novel mechanism of retinoid-induced apoptosis may give a clue to understand the molecular mechanism of clonal deletion.
+ For reprints and all correspondence: Hisataka Moriwaki, First Department of Internal Medicine, Gifu University School of Medicine, Gifu 500-8705, Japan
Abbreviations: AFP-L3, lectin-reactive -fetoprotein; APL, acute promyelocytic leukemia; CCC, cholangiocellular carcinoma; DEN, dimethylnitrosamine; HCC, hepatocellular carcinoma; MAP, mitogen-activated protein; 3'MeDAB, 3'-methyl-4-dimethylaminoazobenzene; RA, retinoic acid; RXR, retinoid X receptor.
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