title: Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1.
abstract: Ovarian cancer patients frequently develop resistance to chemotherapy regiments using Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol-based therapy is multidrug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let-7 family of miRNAs are downregulated in many human cancers, and low let-7 expression has been correlated with resistance to microtubule targeting drugs (Taxanes), although little is known that would explain this activity. We now provide evidence that, although let-7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP-1, resulting in destabilization of the mRNA of MDR1. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non-MDR1 substrate. This effect could be reversed by reintroducing IMP-1 into let-7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let-7 and to co-upregulate IMP-1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease-free time before recurrence. Our data point at IMP-1 and MDR1 as indicators for response to therapy, and at IMP-1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer.
authors: Feinberg School of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
authors: Benjamin
authors: B
authors: Boyerinas
authors: Sun-Mi
authors: SM
authors: Park
authors: Andrea E
authors: AE
authors: Murmann
authors: Katja
authors: K
authors: Gwin
authors: Anton G
authors: AG
authors: Montag
authors: Marion
authors: M
authors: Zillhardt
authors: You-Jia
authors: YJ
authors: Hua
authors: Ernst
authors: E
authors: Lengyel
authors: Marcus E
authors: ME
authors: Peter
references: EMBO J. 2006 Apr 5;25(7):1456-68
references: 16541107
references: Xenobiotica. 2008 Jul;38(7-8):802-32
references: 18668431
references: Nat Rev Cancer. 2009 Mar;9(3):167-81
references: 19238149
references: Mol Cell Biol. 2008 Sep;28(17):5147-61
references: 18573883
references: RNA. 2008 Aug;14(8):1539-49
references: 18566191
references: Biochem J. 2003 Dec 1;376(Pt 2):383-91
references: 12921532
references: Nucleic Acids Res. 2007;35(4):1209-21
references: 17264115
references: Oncogene. 1997 Mar 20;14(11):1279-86
references: 9178888
references: Mol Pharmacol. 2009 Jun;75(6):1374-9
references: 19270061
references: J Neurochem. 2004 May;89(3):613-26
references: 15086518
references: Cancer Res. 2007 Feb 15;67(4):1670-9
references: 17308108
references: EMBO J. 2004 Aug 18;23(16):3346-55
references: 15282548
references: Cancer Res. 2008 Apr 15;68(8):2587-91
references: 18413726
references: Genes Dev. 1992 Apr;6(4):642-54
references: 1559612
references: Antimicrob Agents Chemother. 2007 Aug;51(8):2748-57
references: 17548493
references: Science. 2008 Apr 4;320(5872):97-100
references: 18292307
references: J Biol Chem. 2000 Sep 22;275(38):29562-9
references: 10875929
references: Methods. 2010 Dec;52(4):375-81
references: 20621190
references: Cell. 2007 Dec 14;131(6):1109-23
references: 18083101
references: Curr Cancer Drug Targets. 2009 May;9(3):281-97
references: 19442049
references: Med Oncol. 2010 Jun;27(2):406-15
references: 19412672
references: Nucleic Acids Res. 1998 Nov 15;26(22):5036-44
references: 9801297
references: Scand J Clin Lab Invest Suppl. 2001;234:93-9
references: 11713986
references: Cytometry A. 2003 Jun;53(2):67-78
references: 12766968
references: Mol Cancer Ther. 2008 Jan;7(1):1-9
references: 18187804
references: Blood. 1998 Jun 15;91(12):4480-8
references: 9616142
references: Cancer Res. 2007 Dec 1;67(23):11111-6
references: 18056433
references: Gynecol Oncol. 2008 Nov;111(2):173-8
references: 18823649
references: Biochem Pharmacol. 2008 Sep 1;76(5):582-8
references: 18619946
references: Cancer Res. 2008 Dec 15;68(24):10307-14
references: 19074899
references: Cell. 2009 Jan 23;136(2):215-33
references: 19167326
references: J Biol Chem. 1994 Mar 25;269(12):9261-9
references: 8132663
references: Curr Opin Drug Discov Devel. 2009 Mar;12(2):246-52
references: 19333870
references: Endocr Relat Cancer. 2010 Jan 29;17(1):F19-36
references: 19779035
references: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13513-8
references: 17686970
references: Oncogene. 2003 Oct 20;22(47):7468-85
references: 14576852
references: Mol Cancer Ther. 2009 May;8(5):1055-66
references: 19435871
references: Oncogene. 2007 Nov 29;26(54):7584-9
references: 17546046
references: Nature. 2006 Jun 15;441(7095):898-901
references: 16778892
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11400-5
references: 17600087
references: Biochem Biophys Res Commun. 2007 Sep 21;361(2):301-6
references: 17651695