Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest.
Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.
Lam
T L
TL
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
Wong
G K Y
GK
Chong
H C
HC
Cheng
P N M
PN
Choi
S C
SC
Chow
T L
TL
Kwok
S Y
SY
Poon
R T P
RT
Wheatley
D N
DN
Lo
W H
WH
Leung
Y C
YC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001119:Arginase / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002956:Citrulline / Q000378:metabolism; D020159:Citrullinemia / Q000453:epidemiology; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis; D016213:Cyclins / Q000032:analysis; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000453:epidemiology; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016213:Cyclins; D011994:Recombinant Proteins; D002956:Citrulline; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D001119:Arginase