Heterogeneous gene expression changes in colorectal cancer cells share the WNT pathway in response to growth suppression by APHS-mediated COX-2 inhibition.
Cyclooxygenase-2 (COX-2), the prostaglandin (PG)-synthesizing enzyme overexpressed in colorectal cancer (CRC), has pleiotropic, cancer-promoting effects. COX-2 inhibitors (CIBs) interfere with many cancer-associated processes and show promising antineoplastic activity, however, a common mechanism of CIB action has not yet been established. We therefore investigated by microarray the global response towards the CIB APHS at a dose significantly inhibiting the growth of three COX-2-positive CRC but not of two COX-2-negative cell lines. None of the genes significantly (p = 0.005) affected by APHS were common to all three cell lines and 83% of the altered pathways were cell line-specific. Quantitative polymerase chain reaction (QPCR) on selected pathways confirmed cell line-specific expression alterations induced by APHS. A low stringency data analysis approach using BRB array tools coupled with QPCR, however, identified small expression changes shared by all COX-2-positive cell lines in genes related to the WNT pathway, the key driver of colonic carcinogenesis. Our data indicates a substantial cell line-specificity of APHS-induced expression alterations in CRC cells and helps to explain the divergent effects reported for CIBs. Further, the shared inhibition of the WNT pathway by APHS suggests one potential common mechanism behind the antineoplastic effects of COX-2 inhibition.
Humar
Bostjan
B
Cancer Genetics Laboratory, Department of Biochemistry; University of Otago, Dunedin, Aotearoa New Zealand;
McNoe
Les
L
Dunbier
Anita
A
Heathcott
Rosemary
R
Braithwaite
Antony W
AW
Reeve
Anthony E
AE
Genes Dev. 2005 Apr 15;19(8):877-90
15833914
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11590-5
9751710
Br J Cancer. 2004 Jan 12;90(1):224-9
14710233
Tumour Biol. 2006;27(2):84-91
16582585
Exp Mol Pathol. 2006 Feb;80(1):91-6
15963497
J Biol Chem. 2004 Dec 3;279(49):51581-9
15358764
Mol Cell Biol. 2006 Nov;26(22):8418-26
16954380
Cancer Lett. 2005 Jan 20;217(2):161-9
15617833
Int J Oncol. 2001 Dec;19(6):1179-86
11713587
J Biol Chem. 2005 Jul 15;280(28):26565-72
15899904
J Gastroenterol. 2002;37(3):186-93
11931531
Dig Dis Sci. 2001 Nov;46(11):2314-21
11713928
Cancer Res. 2001 Apr 15;61(8):3465-71
11309309
Cancer Res. 2003 Nov 15;63(22):7613-8
14633677
J Clin Oncol. 2005 Apr 20;23(12):2840-55
15837998
Science. 1998 May 22;280(5367):1268-70
9596581
Mol Cancer Ther. 2006 Jun;5(6):1530-8
16818512
J Natl Cancer Inst. 1991 Jan 2;83(1):29-36
1824600
Cell. 2002 Oct 18;111(2):241-50
12408868
J Biol Chem. 2002 Jan 25;277(4):2614-9
11706038
Nat Rev Drug Discov. 2007 Oct;6(10):793-810
17906642
Oncogene. 2005 Nov 24;24(53):7946-52
16007117
Science. 2005 Dec 2;310(5753):1504-10
16293724
FASEB J. 2005 Aug;19(10):1353-5
15946992
Cancer Res. 1985 Aug;45(8):3790-5
4016751
Cancer Res. 2006 Sep 15;66(18):9245-51
16982769