title: Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1α signaling axis.
abstract: We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1α. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance.
authors.affiliation: Aix-Marseille Université, CRO2, INSERM, UMR 911, Marseille cedex 5, France.
authors.forename: Sadia
authors.initials: S
authors.lastname: Beloribi-Djefaflia
authors.affiliation: Aix-Marseille Université, CRO2, INSERM, UMR 911, Marseille cedex 5, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Siret
authors.affiliation: Aix-Marseille Université, CRO2, INSERM, UMR 911, Marseille cedex 5, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lombardo
keywords: CXCR4-SDF-1α survival axis; Exosomes; cancer cells; lipid rafts; pancreatic neoplasm
references.citation: Int J Cancer. 2009 Sep 1;125(5):1016-26
references.pmid: 19405120
references.citation: EMBO J. 1996 Dec 2;15(23):6541-51
references.pmid: 8978681
references.citation: Cancer Cell. 2012 Jan 17;21(1):105-20
references.pmid: 22264792
references.citation: Clin Cancer Res. 1999 Jan;5(1):119-27
references.pmid: 9918209
references.citation: J Biol Chem. 2009 Mar 20;284(12):8023-32
references.pmid: 19150980
references.citation: Traffic. 2008 Jun;9(6):871-81
references.pmid: 18331451
references.citation: Semin Cell Dev Biol. 2012 Apr;23(2):145-53
references.pmid: 21924373
references.citation: Cancer Discov. 2011 Jul;1(2):158-69
references.pmid: 21984975
references.citation: Nat Rev Cancer. 2012 Jan 19;12(2):121-32
references.pmid: 22257950
references.citation: Clin Cancer Res. 2004 Apr 1;10 (7):2299-306
references.pmid: 15073105
references.citation: PLoS One. 2011;6(6):e20636
references.pmid: 21695188
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):313-23
references.pmid: 18371365
references.citation: J Biochem. 2006 Jul;140(1):13-21
references.pmid: 16877764
references.citation: J Cell Physiol. 2013 May;228(5):1017-24
references.pmid: 23042611
references.citation: Blood. 2005 Sep 1;106(5):1604-11
references.pmid: 15741221
references.citation: J Immunol. 2007 Oct 15;179(8):5024-32
references.pmid: 17911587
references.citation: Cancer Res. 2007 Mar 1;67(5):2187-96
references.pmid: 17332349
references.citation: Bioessays. 2007 Oct;29(10):1039-47
references.pmid: 17876798
references.citation: J Biol Chem. 2012 Nov 9;287(46):39115-24
references.pmid: 22995914
references.citation: Cancer Sci. 2013 Aug;104(8):1127-34
references.pmid: 23679813
references.citation: J Proteomics. 2010 Sep 10;73(10):1907-20
references.pmid: 20601276
references.citation: Blood. 2005 Jan 1;105(1):40-8
references.pmid: 15328152
references.citation: Int J Oncol. 2012 Sep;41(3):855-61
references.pmid: 22710732
references.citation: Pancreas. 2010 Jan;39(1):81-7
references.pmid: 19820417
references.citation: Cell. 2006 Oct 6;127(1):125-37
references.pmid: 16962653
references.citation: Neoplasia. 2012 Aug;14(8):690-701
references.pmid: 22952422
references.citation: Stem Cell Rev. 2011 Jun;7(2):292-306
references.pmid: 21103958
references.citation: Nature. 2003 Oct 23;425(6960):851-6
references.pmid: 14520413
references.citation: J Clin Invest. 2011 Dec;121(12 ):4685-99
references.pmid: 22056382
references.citation: Thromb Res. 2010 Apr;125 Suppl 1:S49-51
references.pmid: 20149923
references.citation: Mol Cell Biol. 2000 Mar;20(5):1626-38
references.pmid: 10669740
references.citation: Transl Oncol. 2012 Oct;5(5):335-43
references.pmid: 23066442
references.citation: Biochimie. 2007 Feb;89(2):205-12
references.pmid: 17157973
references.citation: Cancer Lett. 2013 Oct 28;340(1):113-23
references.pmid: 23872274
references.citation: FASEB J. 2008 Sep;22(9):3358-69
references.pmid: 18511551
references.citation: J Transl Med. 2012 Apr 02;10 :68
references.pmid: 22472349
references.citation: J Immunol. 2002 Apr 15;168(8):4121-6
references.pmid: 11937572
references.citation: Cell Signal. 2011 Oct;23(10):1515-27
references.pmid: 21620960
references.citation: Gastroenterology. 2013 Jun;144(6):1241-8
references.pmid: 23622133
references.citation: Cancer Res. 2005 Jul 1;65(13):5864-71
references.pmid: 15994964
references.citation: Clin Cancer Res. 2011 Apr 15;17(8):2074-80
references.pmid: 21349998
references.citation: J Biol Chem. 2008 Aug 15;283(33):22529-40
references.pmid: 18539594
references.citation: Oncogene. 2003 Mar 6;22(9):1365-70
references.pmid: 12618762
references.citation: Curr Oncol. 2010 Jun;17(3):9-16
references.pmid: 20567622
references.citation: Curr Opin Cell Biol. 2004 Aug;16(4):415-21
references.pmid: 15261674
references.citation: Br J Cancer. 2005 Aug 8;93(3):319-30
references.pmid: 16052215
references.citation: J Cell Biol. 2002 May 27;157(5):865-72
references.pmid: 12021258
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16537-42
references.pmid: 15536134
references.citation: PLoS One. 2012;7(10):e47480
references.pmid: 23094054
references.citation: Cancer Res. 2004 Nov 15;64(22):8420-7
references.pmid: 15548713
references.citation: PLoS Biol. 2007 Apr;5(4):e95
references.pmid: 17407381
references.citation: J Biol Chem. 2010 Dec 3;285(49):38069-77
references.pmid: 20923761
references.citation: Mol Cell Biol. 1999 Jul;19(7):4798-805
references.pmid: 10373529
references.citation: Br J Cancer. 2010 Nov 23;103(11):1671-9
references.pmid: 21045835
references.citation: Cancer Discov. 2013 Jun;3(6):690-703
references.pmid: 23547054
references.citation: Adv Cancer Res. 2011;110:1-17
references.pmid: 21704226