Retinoic acid and its binding protein modulate apoptotic signals in hypoxic hepatocellular carcinoma cells.
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.
Lee
Jeong-Hoon
JH
Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul, Republic of Korea.
Yoon
Jung-Hwan
JH
Yu
Su Jong
SJ
Chung
Goh Eun
GE
Jung
Eun Uk
EU
Kim
Hwi Young
HY
Kim
Bo Hyun
BH
Choi
Dae Hee
DH
Myung
Sun Jung
SJ
Kim
Yoon Jun
YJ
Kim
Chung Yong
CY
Lee
Hyo-Suk
HS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D056811:Unfolded Protein Response
D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin