Enhanced interleukin-2 diphtheria toxin conjugate-induced growth suppression in retinoic acid-treated hypoxic hepatocellular carcinoma cells.
Hypoxia induces survival signals in hepatocellular carcinoma (HCC). Hypoxia and retinoic acid (RA) may also induce interleukin-2 (IL-2) receptor expression, and thus we evaluated if RA and IL-2 receptor-targeted therapy are indicated in hypoxic HCCs. RA induced IL-2 receptor expression (R alpha, R beta, R gamma) in HCC cells, whereas hypoxia specifically induced IL-2 R gamma expression. IL-2 stimulated hypoxic HCC cell growth via p42/44 MAPK activation. Combination of denileukin diftitox and RA significantly suppressed hypoxic HCC cell growth compared to single agent-treated or normoxic cells. Therefore, denileukin diftitox and RA may be therapeutically implicated in infiltrative HCCs which are exposed to hypoxic environments.
Kim
Bo Hyun
BH
Department of Internal Medicine and the Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul 110-744, Republic of Korea.
Yoon
Jung-Hwan
JH
Myung
Sun Jung
SJ
Lee
Jeong-Hoon
JH
Lee
Sung-Hee
SH
Lee
Soo-Mi
SM
Lee
Hyo-Suk
HS
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D004167:Diphtheria Toxin; D007376:Interleukin-2; D014212:Tretinoin; D020928:Mitogen-Activated Protein Kinases