Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis.
Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3'UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Fernando F
FF
Blanco
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Ranjan
R
Preet
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Andrea
A
Aguado
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Vikalp
V
Vishwakarma
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Laura E
LE
Stevens
Maharashtra Cosmopolitan Education Society's ISTRA, Azam Campus, University of Pune, India.
Alok
A
Vyas
Maharashtra Cosmopolitan Education Society's ISTRA, Azam Campus, University of Pune, India.
Subhash
S
Padhye
University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
Liang
L
Xu
Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
Scott J
SJ
Weir
Department of Surgery, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
Shrikant
S
Anant
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Nicole
N
Meisner-Kober
Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Jonathan R
JR
Brody
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.|University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
Dan A
DA
Dixon
D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D000067780:ELAV-Like Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009284:Naphthols / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D005663:Furans; D009284:Naphthols; C096620:5,8-dihydroxy-3-methyl-4-(9H)-naphtho(2,3-c)furanone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
AU-rich elements; HuR; MS-444; RNA stability; colon cancer
Curr Colorectal Cancer Rep. 2010 Apr;6(2):60-67
20577575
Gastroenterology. 2009 May;136(5):1669-79
19208339
Acta Crystallogr D Biol Crystallogr. 2004 Aug;60(Pt 8):1355-63
15272157
Oncogene. 2016 May;35(19):2529-41
26387536
Oncotarget. 2015 Sep 29;6(29):27312-31
26314962
Oncogene. 2003 Oct 16;22(46):7146-54
14562043
Cancer Res. 2010 May 1;70(9):3618-27
20430759
J Biol Chem. 2000 Mar 3;275(9):6628-35
10692471
Nucleic Acids Res. 2000 Apr 15;28(8):1743-50
10734193
J Biol Chem. 2000 Apr 21;275(16):11750-7
10766797
J Gastrointest Surg. 2002 May-Jun;6(3):304-9
12022979
Mol Cell Biol. 2014 Jan;34(2):180-95
24190969
Oncotarget. 2016 Apr 19;7(16):21812-24
26943573
Cancer Res Treat. 2009 Jun;41(2):87-92
19707506
Mol Cell Biol. 2001 Sep;21(17):5889-98
11486028
Gynecol Oncol. 2005 Oct;99(1):14-9
16126263
J Antibiot (Tokyo). 1995 Sep;48(9):948-51
7592060
Mol Cancer Res. 2008 Jul;6(7):1124-36
18644977
J Cell Biol. 2008 Jan 14;180(1):113-27
18180367
Gastroenterology. 2007 Mar;132(3):1055-65
17383427
J Clin Invest. 2001 Dec;108(11):1657-65
11733561
Cell. 2011 Mar 4;144(5):646-74
21376230
EMBO J. 1998 Jun 15;17(12):3461-70
9628881
J Mol Graph Model. 1999 Feb;17(1):57-61
10660911
J Antibiot (Tokyo). 1995 Sep;48(9):952-3
7592061
Br J Cancer. 2011 Mar 1;104(5):819-29
21285980
Carcinogenesis. 2013 Nov;34(11):2610-21
23880304
EMBO J. 1998 Jun 15;17(12):3448-60
9628880
Cancer Res. 2014 Feb 15;74(4):1128-40
24536047
Mol Cancer Res. 2012 Jan;10(1):167-80
22049153
Mol Carcinog. 2000 Jun;28(2):76-83
10900464
Cell. 1990 Jun 1;61(5):759-67
2188735
Mol Cancer Res. 2016 Jul;14 (7):599-611
27053682
J Biol Chem. 1996 Apr 5;271(14):8144-51
8626503
Nat Chem Biol. 2007 Aug;3(8):508-15
17632515
Prog Exp Tumor Res. 2003;37:52-71
12795048
Wiley Interdiscip Rev RNA. 2012 Sep-Oct;3(5):719-31
22733578
Cancer Res. 2016 Mar 15;76(6):1549-59
26921342
J Biol Chem. 2010 May 28;285(22):16806-13
20353946
Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):373-80
23519412
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15293-8
9860962
Mol Cell Biol. 1996 Mar;16(3):884-91
8622690
Cancer Biol Ther. 2012 Aug;13(10):946-55
22785201
J Comput Chem. 2010 Jan 30;31(2):455-61
19499576
ACS Chem Biol. 2015 Jun 19;10(6):1476-84
25750985
EMBO J. 1997 Apr 15;16(8):2130-9
9155038
Med Oncol. 2011 Dec;28 Suppl 1:S577-85
21046284
Biomark Insights. 2007 Feb 14;2:59-68
19662192
Cell Death Differ. 2013 Jan;20(1):154-68
22955946
Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29
21935886
Adv Exp Med Biol. 2010;700:106-23
21627034
Nat Struct Biol. 2001 Feb;8(2):141-5
11175903
Cell Cycle. 2007 Jun 1;6(11):1288-92
17534146
Cancer Biol Ther. 2008 Sep;7(9):1496-506
18769129
EMBO J. 2000 May 15;19(10):2340-50
10811625
Wiley Interdiscip Rev RNA. 2011 May-Jun;2(3):435-44
21957028
Curr Drug Targets. 2015;16(5):499-515
25706256
Cancer Res. 2000 Nov 1;60(21):6045-51
11085526
Mod Pathol. 2006 Sep;19(9):1261-9
16799479
Mol Biol Cell. 2011 Sep;22(17):3055-69
21737690
J Biol Chem. 2000 Oct 27;275(43):33951-6
10930401
Nat Rev Mol Cell Biol. 2007 Feb;8(2):113-26
17245413
Cancer Res. 2005 Mar 15;65(6):2157-61
15781626
Aging (Albany NY). 2009 Sep 10;1(9):803-17
20157568