title: The mitochondrial protein C1qbp promotes cell proliferation, migration and resistance to cell death.
abstract: Complement 1q-Binding Protein (C1qbp) is a mitochondrial protein reported to be upregulated in cancer. However, whether C1qbp plays a tumor suppressive or tumorigenic role in the progression of cancer is controversial. Moreover, the exact effects of C1qbp on cell proliferation, migration, and death/survival have not been definitely proven. To this end, we comprehensively examined the effects of C1qbp on mitochondrial-dependent cell death, proliferation, and migration in both normal and breast cancer cells using genetic gain- and loss-of-function approaches. In normal fibroblasts, overexpression of C1qbp protected the cells against staurosporine-induce apoptosis, increased proliferation, decreased cellular ATP, and increased cell migration in a wound-healing assay. In contrast, the opposite effects were observed in fibroblasts depleted of C1qbp by RNA interference. C1qbp expression was found to be markedly elevated in 4 different human breast cancer cell lines as well as in ductal and adenocarcinoma tumors from breast cancer patients. Stable knockdown of C1qbp by shRNA in the aggressive MDA-MB-231 breast cancer cell line greatly reduced cell proliferation, increased ATP levels, and decreased cell migration compared to control shRNA-transfected cells. Moreover, C1qbp knockdown elicited a significant increase in doxorubicin-induced apoptosis in the MDA-MB-231 cells. Finally, C1qbp upregulation was not restricted to breast cancer cells and tumors, as levels of C1qbp were also found to be significantly elevated in both human lung and colon cancer cell lines and carcinomas. Together, these results establish a pro-tumor, rather than anti-tumor, role for C1qbp, and indicate that C1qbp could serve as a molecular target for cancer therapeutics.
authors.affiliation: Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: McGee
authors.forename: Diana L
authors.initials: DL
authors.lastname: Douglas
authors.forename: Yayun
authors.initials: Y
authors.lastname: Liang
authors.forename: Salman M
authors.initials: SM
authors.lastname: Hyder
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Baines
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002465:Cell Movement; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D014945:Wound Healing
chemical_list: C087299:C1QBP protein, human; C490193:C1qbp protein, mouse; D002352:Carrier Proteins; D018960:Hyaluronan Receptors; D024101:Mitochondrial Proteins; D004317:Doxorubicin; D019311:Staurosporine
references.citation: Adv Drug Deliv Rev. 2001 Jul 2;49(1-2):87-105
references.pmid: 11377805
references.citation: Biochem J. 2005 Feb 15;386(Pt 1):119-25
references.pmid: 15456408
references.citation: Immunol Rev. 2001 Apr;180:65-77
references.pmid: 11414365
references.citation: Nature. 2005 Mar 31;434(7033):658-62
references.pmid: 15800627
references.citation: Cancer Res. 2008 Sep 1;68(17):7210-8
references.pmid: 18757437
references.citation: Blood. 2010 Feb 11;115(6):1238-46
references.pmid: 20007804
references.citation: Yeast. 1998 Mar 15;14(4):303-10
references.pmid: 9559539
references.citation: Cell Mol Life Sci. 2009 May;66(10):1755-65
references.pmid: 19337692
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107(19):8788-93
references.pmid: 20421486
references.citation: Exp Cell Res. 2008 Feb 1;314(3):651-67
references.pmid: 18166172
references.citation: J Immunol. 1998 Apr 1;160(7):3534-42
references.pmid: 9531316
references.citation: Free Radic Biol Med. 2011 Aug 15;51(4):893-904
references.pmid: 21703345
references.citation: Int J Cancer. 2004 Jul 10;110(5):741-50
references.pmid: 15146564
references.citation: Cancer Sci. 2011 Mar;102(3):639-47
references.pmid: 21205079
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4675-80
references.pmid: 20176937
references.citation: Cell Res. 2005 Mar;15(3):183-6
references.pmid: 15780180
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Apoptosis. 2006 May;11(5):861-74
references.pmid: 16544101
references.citation: Carcinogenesis. 2008 Sep;29(9):1742-50
references.pmid: 18632752
references.citation: J Biol Chem. 1981 Nov 10;256(21):10924-9
references.pmid: 6974732
references.citation: J Biol Chem. 1997 Sep 26;272(39):24363-70
references.pmid: 9305894
references.citation: FASEB J. 2010 Feb;24(2):464-78
references.pmid: 19812375
references.citation: Thromb Haemost. 2004 Oct;92(4):811-9
references.pmid: 15467913
references.citation: J Cell Sci. 2001 Jun;114(Pt 11):2115-23
references.pmid: 11493647
references.citation: Cancer Res. 2009 Mar 15;69(6):2375-83
references.pmid: 19276362
references.citation: Ann N Y Acad Sci. 2010 Jul;1201:137-46
references.pmid: 20649550
references.citation: Mol Cell Biol. 2010 Mar;30(6):1303-18
references.pmid: 20100866
references.citation: Biochem J. 2011 Jan 1;433(1):119-25
references.pmid: 20950273
references.citation: Cell Death Differ. 2004 Jul;11(7):771-81
references.pmid: 15031724
references.citation: J Surg Oncol. 2009 Oct 1;100(5):382-6
references.pmid: 19565630
references.citation: J Biol Chem. 2011 Feb 18;286(7):5197-203
references.pmid: 21156793
references.citation: Nucleic Acids Res. 2004 Jul 08;32(12):3632-41
references.pmid: 15243141
references.citation: Cancer Lett. 2007 Dec 18;258(2):181-8
references.pmid: 17920763
references.citation: Cancer Cell. 2008 Jun;13(6):542-53
references.pmid: 18538737
references.citation: Biochim Biophys Acta. 2011 Jun;1807(6):534-42
references.pmid: 20849810