title: Bisphosphorylated PEA-15 sensitizes ovarian cancer cells to paclitaxel by impairing the microtubule-destabilizing effect of SCLIP.
abstract: Paclitaxel is a standard chemotherapeutic agent for ovarian cancer. PEA-15 (phosphoprotein enriched in astrocytes-15 kDa) regulates cell proliferation, autophagy, apoptosis, and glucose metabolism and also mediates AKT-dependent chemoresistance in breast cancer. The functions of PEA-15 are tightly regulated by its phosphorylation status at Ser104 and Ser116. However, the effect of PEA-15 phosphorylation status on chemosensitivity of cancer cells remains unknown. Here, we tested the hypothesis that PEA-15 phosphorylated at both Ser104 and Ser116 (pPEA-15) sensitizes ovarian cancer cells to paclitaxel. We first found that knockdown of PEA-15 in PEA-15-high expressing HEY and OVTOKO ovarian cancer cells resulted in paclitaxel resistance, whereas re-expression of PEA-15 in these cells led to paclitaxel sensitization. We next found that SKOV3.ip1-DD cells (expressing phosphomimetic PEA-15) were more sensitive to paclitaxel than SKOV3.ip1-AA cells (expressing nonphosphorylatable PEA-15). Compared with SKOV3.ip1-vector and SKOV3.ip1-AA cells, SKOV3.ip1-DD cells displayed reduced cell viability, inhibited anchorage-independent growth, and augmented apoptosis when treated with paclitaxel. Furthermore, HEY and OVTOKO cells displayed enhanced paclitaxel sensitivity when transiently overexpressing phosphomimetic PEA-15 and reduced paclitaxel sensitivity when transiently overexpressing nonphosphorylatable PEA-15. These results indicate that pPEA-15 sensitizes ovarian cancer cells to paclitaxel. cDNA microarray analysis suggested that SCLIP (SCG10-like protein), a microtubule-destabilizing protein, is involved in pPEA-15-mediated chemosensitization. We found that reduced expression and possibly posttranslational modification of SCLIP following paclitaxel treatment impaired the microtubule-destabilizing effect of SCLIP, thereby promoting induction of mitotic arrest and apoptosis by paclitaxel. Our findings highlight the importance of pPEA-15 as a promising target for improving the efficacy of paclitaxel-based therapy in ovarian cancer.
authors.affiliation: Section of Translational Breast Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xie
authors.forename: Chandra
authors.initials: C
authors.lastname: Bartholomeusz
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ahmed
authors.forename: Anna
authors.initials: A
authors.lastname: Kazansky
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; C112285:STMN3 protein, human; D050777:Stathmin; D017239:Paclitaxel
references.citation: Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9552-6
references.pmid: 8105478
references.citation: J Cell Biol. 1987 Jul;105(1):251-64
references.pmid: 2886509
references.citation: J Biol Chem. 2006 Jan 27;281(4):2071-8
references.pmid: 16317007
references.citation: Oncogene. 2012 Jul 26;31(30):3547-60
references.pmid: 22105357
references.citation: Mol Cell Biol. 2003 Jul;23(13):4511-21
references.pmid: 12808093
references.citation: Expert Opin Pharmacother. 2002 Jun;3(6):755-66
references.pmid: 12036415
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11737-42
references.pmid: 11562465
references.citation: J Cell Sci. 1998 Nov;111 ( Pt 22):3333-46
references.pmid: 9788875
references.citation: Cancer Res. 2000 Sep 15;60(18):5171-8
references.pmid: 11016645
references.citation: Nat Rev Cancer. 2004 Apr;4(4):253-65
references.pmid: 15057285
references.citation: J Neurochem. 1978 Jul;31(1):205-10
references.pmid: 671018
references.citation: J Neurochem. 1998 Sep;71(3):1307-14
references.pmid: 9721757
references.citation: J Neurosci. 1989 Jan;9(1):358-68
references.pmid: 2563279
references.citation: J Inorg Biochem. 2012 Dec;117:277-84
references.pmid: 22819650
references.citation: Cancer Res. 2004 Oct 15;64(20):7562-9
references.pmid: 15492283
references.citation: Biochemistry. 1997 Sep 9;36(36):10817-21
references.pmid: 9312271
references.citation: Oncogenesis. 2012 Jul 16;1:e22
references.pmid: 23552738
references.citation: Oncogene. 2003 Dec 4;22(55):8924-30
references.pmid: 14654788
references.citation: Dev Biol. 1999 Dec 1;216(1):16-28
references.pmid: 10588860
references.citation: Mol Cell. 2002 May;9(5):993-1004
references.pmid: 12049736
references.citation: Cancer Res. 2005 Aug 1;65(15):6668-75
references.pmid: 16061647
references.citation: Cancer Res. 2011 Sep 1;71(17):5806-17
references.pmid: 21775522
references.citation: Cancer Res. 2007 Feb 15;67(4):1536-44
references.pmid: 17308092
references.citation: Mol Biol Cell. 2005 Aug;16(8):3552-61
references.pmid: 15917297
references.citation: J Cell Biol. 1981 Nov;91(2 Pt 1):479-87
references.pmid: 6118377
references.citation: Cell. 1996 Feb 23;84(4):623-31
references.pmid: 8598048
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: J Cell Sci. 2001 Mar;114(Pt 5):909-16
references.pmid: 11181174
references.citation: Proc Natl Acad Sci U S A. 1987 Aug;84(16):5720-4
references.pmid: 2441392
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10166-10173
references.pmid: 16801540
references.citation: Curr Opin Cell Biol. 2002 Feb;14(1):18-24
references.pmid: 11792540
references.citation: Cancer Res. 2008 Nov 15;68(22):9302-10
references.pmid: 19010903
references.citation: J Biol Chem. 1997 Jul 4;272(27):17118-25
references.pmid: 9202030
references.citation: Mol Biol Cell. 1999 Apr;10(4):947-59
references.pmid: 10198049
references.citation: Clin Cancer Res. 2010 Mar 15;16(6):1802-11
references.pmid: 20215547
references.citation: Int J Cancer. 2008 Jan 1;122(1):1-4
references.pmid: 17960586
references.citation: Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E592-601
references.pmid: 19531639
references.citation: Mol Pharmacol. 2007 May;71(5):1233-40
references.pmid: 17272681
references.citation: J Proteomics. 2010 Mar 10;73(5):879-98
references.pmid: 19951750
references.citation: J Biol Chem. 2001 May 11;276(19):16146-54
references.pmid: 11278715
references.citation: Cancer Res. 2002 Dec 1;62(23):6864-9
references.pmid: 12460900
references.citation: Subcell Biochem. 2006;40:355-8
references.pmid: 17623920
references.citation: Int J Nanomedicine. 2011;6:203-11
references.pmid: 21445276
references.citation: Expert Opin Investig Drugs. 2007 Aug;16(8):1227-39
references.pmid: 17685871