title: Bioengineered arginase I increases caspase-3 expression of hepatocellular and pancreatic carcinoma cells despite induction of argininosuccinate synthetase-1.
abstract: BACKGROUND
  Hepatocellular and pancreatic carcinomas are often auxotrophic for L-arginine, a semi-essential amino acid. The purpose of this study was to investigate cancer cell death using a significantly more active, cobalt-substituted bioengineered arginase.
  
  
  METHODS
  Panc-1, a human pancreatic carcinoma cell line, and Hep 3B, a human hepatocellular carcinoma cell line, were exposed to L-arginase. Flow cytometry was used to measure expression of Ki-67, caspase-3, and argininosuccinate synthetase-1 (ASS-1) 4 days after treatment. An MTT assay measured proliferation. The Student t test determined statistical significance.
  
  
  RESULTS
  Viability decreased by 31% +/- 2% for Panc-1 cells (P < .0001) and 34% +/- 1% (P < .0001) for Hep 3B cells after treatment. Both cell lines demonstrated a 4-fold increase activated caspase-3 expression after high dose treatment (P < .01), and 5-fold increase in ASS-1 expression (P < .002). Ki-67 expression did not vary in Hep 3B cells but decreased for Panc-1 cells (P < .015). The 50% inhibitory concentration was 8-fold higher for Panc-1 cells than for Hep 3B cells (P < .03).
  
  
  CONCLUSIONS
  Increased ASS-1 expression by these cells, in order to increase L-arginine concentration, is inadequate, suggesting a mechanism by which arginine depletion can be used in multimodality therapy for arginine-dependent cancers.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Glazer
authors.forename: Warna D
authors.initials: WD
authors.lastname: Kaluarachchi
authors.forename: Katheryn L
authors.initials: KL
authors.lastname: Massey
authors.forename: Cihui
authors.initials: C
authors.lastname: Zhu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001119:Arginase / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D001124:Argininosuccinate Synthase / Q000096:biosynthesis*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D019394:Ki-67 Antigen; D011994:Recombinant Proteins; D001120:Arginine; C505407:CASP3 protein, human; D053148:Caspase 3; D001119:Arginase; D001124:Argininosuccinate Synthase
references.citation: Cancer. 2004 Feb 15;100(4):826-33
references.pmid: 14770441
references.citation: Hum Reprod. 2006 Jan;21(1):193-201
references.pmid: 16210392
references.citation: Curr Pharm Des. 2008;14(11):1049-57
references.pmid: 18473854
references.citation: Cancer Lett. 2005 Jun 16;224(1):67-80
references.pmid: 15911102
references.citation: Blood. 1994 Sep 1;84(5):1415-20
references.pmid: 8068938
references.citation: Autophagy. 2009 May;5(4):567-8
references.pmid: 19276647
references.citation: Nutrition. 1990 Jan-Feb;6(1):53-8; discussion 59-62
references.pmid: 2135757
references.citation: Cancer Res. 1993 Apr 15;53(8):1945-51
references.pmid: 8467513
references.citation: J Clin Oncol. 2010 May 1;28(13):2220-6
references.pmid: 20351325
references.citation: Oncologist. 2007 Aug;12(8):991-8
references.pmid: 17766659
references.citation: Int J Cancer. 2008 Oct 15;123(8):1950-5
references.pmid: 18661517
references.citation: Mamm Genome. 1998 Oct;9(10):822-4
references.pmid: 9745037
references.citation: Hepatogastroenterology. 2003 Sep-Oct;50(53):1214-6
references.pmid: 14571701
references.citation: Cancer Res. 1990 Aug 1;50(15):4522-7
references.pmid: 2164440
references.citation: Tissue Eng Part A. 2009 Aug;15(8):2001-13
references.pmid: 19292684
references.citation: Cancer Res. 2007 Jan 1;67(1):309-17
references.pmid: 17210712
references.citation: Int J Cancer. 2007 Feb 15;120(4):897-905
references.pmid: 17096330
references.citation: Br J Cancer. 2007 Feb 12;96(3):445-9
references.pmid: 17245336
references.citation: Science. 1941 Aug 8;94(2432):144
references.pmid: 17744598
references.citation: ACS Chem Biol. 2010 Mar 19;5(3):333-42
references.pmid: 20050660
references.citation: J Clin Oncol. 2004 May 15;22(10):1815-22
references.pmid: 15143074