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Retinoic acid and its binding protein modulate apoptotic signals in hypoxic hepatocellular carcinoma cells

2010; Elsevier BV; Volume: 295; Issue: 2 Linguagem: Inglês

10.1016/j.canlet.2010.03.005

1872-7980

Jeong‐Hoon Lee, Jung‐Hwan Yoon, Su Jong Yu, Goh Eun Chung, Eun Uk Jung, Hwi Young Kim, Bo Hyun Kim, Dae Hee Choi, Sun Jung Myung, Yoon Jun Kim, Chung Yong Kim, Hyo-Suk Lee,

Ubiquitin and proteasome pathways

Hypoxia induces survival signals in hepatocellular carcinoma (HCC). We attempted to find a hypoxia-induced signal that could be used for modulating HCC cell death. Cellular retinoic acid binding protein-II (CRABP-II) expression was significantly increased in hypoxic HCC cells. Treatment with retinoic acid (RA), a ligand for CRABP-II, induced HCC cell apoptosis more effectively in hypoxia than in normoxia, whereas hypoxia-induced CRABP-II expression attenuated RA-induced apoptosis. Inhibition of CRABP-II enhanced RA-induced apoptosis and sensitized RA-resistant HCC cells to RA cytotoxicity by attenuating p42/44 MAPK and Akt activation. Therefore, RA/CRABP-II signal modulation is therapeutically implicated in infiltrative HCCs exposed to hypoxia.