title: Cell cycle and apoptosis regulatory protein (CARP)-1 is a novel, adriamycin-inducible, diffuse large B-cell lymphoma (DLBL) growth suppressor.
abstract: Diffuse large B-cell lymphoma (DLCL) accounts for 30-40% of adult non-Hodgkin's Lymphoma (NHL). Current anti-NHL therapies often target cellular growth suppression pathways and include R-CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone plus monoclonal anti-CD20 antibody rituximab). However, since many patients relapse, resistant cells to these therapies remain a significant problem and necessitate development of new intervention strategies. Cell cycle and apoptosis regulatory protein (CARP)-1 functions in a biphasic manner to regulate growth factor as well as chemotherapy (adriamycin, etoposide, or iressa)-dependent signaling.
  
  
  OBJECTIVE
  To determine whether CARP-1 is a novel suppressor of lymphoma growth.
  
  
  METHODS
  Flow cytometric analyses coupled with Western immunoblotting, cell growth, apoptosis, and immunocytochemistry methodologies were utilized to determine CARP-1-dependent lymphoma growth inhibition in vitro and in vivo.
  
  
  RESULTS
  CARP-1 expression correlated with activated caspase-3 and inversely correlated with activated Akt in DLCL. Exposure to adriamycin stimulated CARP-1 expression and inhibited growth of Raji cells, but not CHOP-resistant WSU-DLCL2 cells. Expression of wild-type CARP-1 or its apoptosis-inducing mutants inhibited growth of Raji as well as CHOP-resistant WSU-DLCL2 cells, in part by activating caspase-9 and apoptosis. Since CARP-1 harbors multiple, apoptosis-promoting subdomains, we investigated whether epigenetic compensation of CARP-1 function by intracellular delivery of trans-activator of transcription (TAT) domain-tagged CARP-1 peptide(s) will inhibit lymphoma growth. Treatments with TAT-tagged CARP-1 peptides suppressed growth of the Raji and WSU-DLCL2 cells by stimulating apoptosis. TAT-CARP-1 (1-198) as well as (896-1150) peptides also suppressed growth of WSU-DLCL2 cell-derived tumor xenografts in SCID mice, while administration of TAT-CARP-1 (1-198) also inhibited growth of WSU-FSCCL cell-derived ascites and prolonged host survival.
  
  
  CONCLUSIONS
  CARP-1 is a suppressor of NHL growth and could be exploited for targeting the resistant DLCL.
authors.affiliation: Room B4334, Veterans Affairs Medical Center, Wayne State University, 4646 John R, Detroit, MI 48201, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.forename: Liyue
authors.initials: L
authors.lastname: Zhang
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Sunny
authors.initials: S
authors.lastname: Rishi
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: James S
authors.initials: JS
authors.lastname: Hatfield
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D010446:Peptide Fragments; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
references.citation: Clin Cancer Res. 2000 Dec;6(12):4950-6
references.pmid: 11156256
references.citation: Blood. 1997 Oct 15;90(8):3167-72
references.pmid: 9376599
references.citation: Sci STKE. 2004 Jun 22;2004(239):re9
references.pmid: 15226512
references.citation: J Biol Chem. 1999 Mar 5;274(10):6469-75
references.pmid: 10037739
references.citation: Mol Cancer Ther. 2007 May;6(5):1661-72
references.pmid: 17513614
references.citation: J Biol Chem. 2009 Jul 31;284(31):20629-37
references.pmid: 19520846
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5
references.pmid: 15302935
references.citation: Nat Med. 2002 Jan;8(1):68-74
references.pmid: 11786909
references.citation: Leukemia. 2000 May;14(5):898-904
references.pmid: 10803523
references.citation: PLoS Biol. 2004 Feb;2(2):E36
references.pmid: 14966535
references.citation: J Clin Oncol. 1999 Jan;17(1):423-9
references.pmid: 10458261
references.citation: J Biol Chem. 2003 Aug 29;278(35):33422-35
references.pmid: 12816952
references.citation: Mol Cell. 2008 Aug 22;31(4):510-519
references.pmid: 18722177
references.citation: Adv Drug Deliv Rev. 2005 Feb 28;57(4):579-96
references.pmid: 15722165
references.citation: Mol Cancer Ther. 2004 Dec;3(12):1693-9
references.pmid: 15634664
references.citation: Science. 2007 May 25;316(5828):1160-6
references.pmid: 17525332
references.citation: Nature. 2000 Feb 3;403(6769):503-11
references.pmid: 10676951
references.citation: BMC Cancer. 2005 Aug 18;5:103
references.pmid: 16109167
references.citation: Science. 1999 Sep 3;285(5433):1569-72
references.pmid: 10477521
references.citation: J Pept Sci. 2005 Nov;11(11):713-26
references.pmid: 16138387
references.citation: Nat Biotechnol. 2003 Mar;21(3):315-8
references.pmid: 12577067
references.citation: Blood. 1997 Jun 1;89(11):3909-18
references.pmid: 9166827
references.citation: J Biol Chem. 2006 May 12;281(19):13188-13198
references.pmid: 16543231
references.citation: Cancer Genet Cytogenet. 1993 Oct 1;70(1):62-7
references.pmid: 8221615
references.citation: Anticancer Drugs. 1998 Feb;9(2):149-56
references.pmid: 9510501