Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis.
Melanoma is the most lethal form of human skin cancer. However, only limited chemotherapy is currently available for the metastatic stage of the disease. Since chemotherapy, radiation and sodium arsenite treatment operate mainly through induction of the intrinsic mitochondrial pathway, a strongly decreased mitochondrial function in metastatic melanoma cells, could be responsible for low efficacy of the conventional therapy of melanoma. Another feature of metastatic melanoma cells is their proinflammatory phenotype, linked to endogenous expression of the inflammatory cytokines, such as TNFα IL6 and IL8, their receptors, and constitutive NF-κB- and STAT3-dependent gene expression, including cyclooxygenase-2 (PTGS2/COX2). In the present study, we treated melanoma cells with immunological (monoclonal antibody against TNFα or IL6), pharmacological (small molecular inhibitors of IKKβ-NF-κB and JAK2-STAT3) or genetic (specific RNAi for COX-2) agents that suppressed the inflammatory response in combination with induction of apoptosis via TRAIL. As a result of these combined treatments, exogenous TRAIL via interactions with TRAIL-R2/R1 strongly increased levels of apoptosis in resistant melanoma cells. The present study provides new understanding of the regulation of TRAIL-mediated apoptosis in melanoma and will serve as the foundation for the potential development of a novel approach for a therapy of resistant melanomas.
Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. vni3@columbia.edu
Vladimir N
VN
Ivanov
Michael A
MA
Partridge
Sarah X L
SX
Huang
Tom K
TK
Hei
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D051546:Cyclooxygenase 2
Cancer Res. 2006 Dec 1;66(23):11115-9
17145853
Clin Sci (Lond). 2004 Oct;107(4):355-64
15279618
Cancer Res. 2002 Dec 15;62(24):7335-42
12499277
Oncogene. 2000 Feb 17;19(7):933-42
10702802
Int J Cancer. 1994 Mar 15;56(6):853-7
7509778
Oncogene. 2003 Jun 26;22(26):4092-101
12821943
Melanoma Res. 1997 Aug;7 Suppl 2:S35-42
9578415
Oncologist. 2004;9(2):182-7
15047922
Cold Spring Harb Perspect Biol. 2009 Nov;1(5):a000141
20066113
Exp Cell Res. 2008 Mar 10;314(5):1163-76
18222423
Genes Dev. 2007 Jun 1;21(11):1396-408
17510282
Cancer Res. 2006 Mar 1;66(5):2544-52
16510571
Oncogene. 2003 May 19;22(20):3113-22
12789288
Nat Rev Drug Discov. 2010 Jun;9(6):447-64
20467424
Mol Cancer Ther. 2009 Mar;8(3):636-47
19276165
Mol Cancer Res. 2010 Feb;8(2):232-45
20145033
J Invest Dermatol. 2008 Jun;128(6):1499-505
18079751
Exp Cell Res. 2006 May 1;312(8):1401-17
16487513
J Clin Invest. 2005 Oct;115(10):2625-32
16200195
Cell. 2006 Feb 24;124(4):823-35
16497591
Cancer Cell. 2008 Jan;13(1):7-9
18167335
Dermatol Clin. 2002 Oct;20(4):601-6
12380047
Oncogene. 2009 Feb 19;28(7):961-72
19137011
Oncogene. 2003 May 19;22(20):3138-51
12789290
Cancer Res. 2004 Jan 1;64(1):337-46
14729643
Oncogene. 2006 Aug 7;25(34):4798-811
16892092
Oncogene. 2003 May 19;22(20):3152-61
12789291
Cancer Res. 2003 Feb 15;63(4):756-9
12591721
Int Rev Cytol. 2006;251:131-58
16939779
J Cell Biol. 2006 Dec 18;175(6):913-23
17158952
Nat Rev Cancer. 2009 Nov;9(11):798-809
19851315
J Am Acad Dermatol. 1996 May;34(5 Pt 1):839-47
8632084
Nat Rev Cancer. 2002 Oct;2(10):740-9
12360277
Mol Cell Biol. 2001 Jun;21(12):3964-73
11359904
Blood. 2003 Aug 1;102(3):1028-34
12676792
J Bioenerg Biomembr. 2004 Aug;36(4):381-6
15377876
Cancer. 2007 Feb 1;109(3):455-64
17200963
Biochim Biophys Acta. 2002 Jan 30;1542(1-3):14-22
11853875
Genes Dev. 2006 Aug 15;20(16):2149-82
16912270
Cancer Res. 2007 Jun 1;67(11):5397-407
17545621
J Hepatol. 2007 Oct;47(4):546-55
17602782
Cancer Res. 2009 Apr 15;69(8):3510-9
19351839
Nature. 2002 Dec 19-26;420(6917):860-7
12490959
J Biol Chem. 2004 May 21;279(21):22747-58
15028728
Exp Cell Res. 2006 Dec 10;312(20):4120-38
17070520
Trends Pharmacol Sci. 2003 Feb;24(2):96-102
12559775
Exp Cell Res. 2007 Feb 1;313(3):551-9
17141217
Curr Med Res Opin. 2005 Mar;21(3):403-11
15811209
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):950-60
16467110
Oncogene. 2005 Jan 20;24(4):616-26
15580309
Anticancer Res. 2004 Sep-Oct;24(5A):2783-840
15517885
Mol Cell. 2001 Mar;7(3):517-28
11463377
Clin Cancer Res. 2007 Apr 15;13(8):2422-8
17438101
Cancer Res. 2007 Jun 1;67(11):5239-47
17545603
J Natl Cancer Inst. 2000 Jul 5;92(13):1042-53
10880547
Genes Dev. 2009 Mar 1;23(5):537-48
19270154
J Clin Oncol. 2008 Jul 20;26(21):3621-30
18640940
Front Biosci. 2007 May 01;12:3813-24
17485341
Oncogene. 2000 Apr 13;19(16):2014-22
10803462