title: p38δ MAPK phenotype: an indicator of chemotherapeutic response in oesophageal squamous cell carcinoma.
abstract: We recently documented p38δ differential expression and function in oesophageal squamous cell carcinoma (OESCC). This study expands upon these findings and investigates whether p38δ status in OESCC can influence response(s) to cytotoxic drugs. The antiproliferative effect of conventional cisplatin and 5-fluorouracil (CF) treatment was compared with the recently reviewed triple regime of cisplatin, 5-fluorouracil and doxorubicin (ACF). p38δ-positive and p38δ-negative cell lines were employed using cell-growth and clonogenic assays. Key regulators of intrinsic and extrinsic apoptotic pathways were measured. Wound-healing assays and a Boyden chamber were used to investigate the effect of drug treatments on cell migration. Functional networks were analysed in terms of changes in MAPK expression. p38δ-negative OESCC is less sensitive to standard CF chemotherapy compared with p38δ-positive cells. However, following ACF treatment p38δ-negative cells showed markedly decreased proliferation and cell migration, and increased apoptosis. ACF induced apoptosis through the extrinsic pathway involving Fas activation, caspase-8 and caspase-3 cleavage and degradation of PARP. Loss of mitochondrial membrane potential (ΔΨm) was observed but downregulation of multidomain proapoptotic proteins, as well as BH3-only proteins, suggests involvement of pathways other than the mitochondrial pathway. Interestingly, induction of p38 and ERK1/2, but not JNK1/2, was observed following ACF treatment. p38δ-negative OESCC is more resistant to traditional CF treatment compared with p38δ-positive OESCC. In light of these results, p38δ phenotyping of tumour tissue may be of considerable value in deciding on an optimal therapeutic strategy for patients with p38δ-negative OESCC.
authors.affiliation: Departments of aPharmacology and Therapeutics bMedicine, University College Cork, Cork, Ireland.
authors.forename: Carol
authors.initials: C
authors.lastname: O'Callaghan
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Fanning
authors.forename: Orla P
authors.initials: OP
authors.lastname: Barry
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010641:Phenotype; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin; D005472:Fluorouracil
references.citation: Semin Radiat Oncol. 2013 Jan;23(1):24-30
references.pmid: 23207044
references.citation: Cancer Lett. 2007 Jun 18;251(1):1-16
references.pmid: 17125914
references.citation: Acta Med Okayama. 2002 Jun;56(3):129-34
references.pmid: 12108583
references.citation: Anticancer Res. 2013 Sep;33(9):4123-8
references.pmid: 24023359
references.citation: Carcinogenesis. 2002 Nov;23(11):1831-8
references.pmid: 12419831
references.citation: Int J Oncol. 2013 Aug;43(2):405-15
references.pmid: 23722928
references.citation: Radiat Oncol. 2012 Jan 03;7:1
references.pmid: 22214341
references.citation: Cancer Res. 1995 Oct 1;55(19):4248-52
references.pmid: 7671230
references.citation: Oncology. 2000 Nov;59(4):336-43
references.pmid: 11096347
references.citation: Jpn J Clin Oncol. 2013 Jul;43(7):752-5
references.pmid: 23625063
references.citation: Ann Thorac Cardiovasc Surg. 2006 Oct;12(5):305-7
references.pmid: 17095970
references.citation: Scand J Gastroenterol. 2005 Aug;40(8):886-92
references.pmid: 16170897
references.citation: Methods Mol Biol. 2011;731:219-36
references.pmid: 21516411
references.citation: Microbiol Mol Biol Rev. 2011 Mar;75(1):50-83
references.pmid: 21372320
references.citation: Anticancer Res. 2008 Jul-Aug;28(4C):2321-6
references.pmid: 18751413
references.citation: Ann Surg Oncol. 2010 Feb;17(2):634-42
references.pmid: 19941080
references.citation: Semin Oncol. 1992 Dec;19(6):670-86
references.pmid: 1462166
references.citation: Oncogene. 2012 Mar 1;31(9):1073-85
references.pmid: 21841826
references.citation: PLoS One. 2008 Jun 04;3(6):e2355
references.pmid: 18523641
references.citation: Gan To Kagaku Ryoho. 1994 May;21(6):755-60
references.pmid: 8185331
references.citation: Expert Opin Pharmacother. 2013 Jul;14(10):1345-54
references.pmid: 23675862
references.citation: J Biol Chem. 1995 Nov 17;270(46):27489-94
references.pmid: 7499206
references.citation: Dis Esophagus. 2010 Nov;23(8):641-5
references.pmid: 20545978
references.citation: Autophagy. 2011 May;7(5):509-24
references.pmid: 21325880
references.citation: PLoS One. 2013;8(1):e54181
references.pmid: 23349819
references.citation: Eur J Biochem. 1999 Sep;264(3):687-701
references.pmid: 10491114
references.citation: Cancer Res. 2004 Aug 1;64(15):5442-8
references.pmid: 15289353
references.citation: Eur J Surg Oncol. 2011 Sep;37(9):747-53
references.pmid: 21839394
references.citation: Cell Signal. 2000 Jan;12(1):1-13
references.pmid: 10676842
references.citation: Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):671-7
references.pmid: 23773390
references.citation: Nat Rev Cancer. 2009 Aug;9(8):537-49
references.pmid: 19629069
references.citation: Oncogene. 2007 May 14;26(22):3100-12
references.pmid: 17496909
references.citation: J Clin Pathol. 2006 Jan;59(1):101-4
references.pmid: 16394289
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1358-75
references.pmid: 17481747
references.citation: Apoptosis. 2011 Feb;16(2):174-83
references.pmid: 21082354
references.citation: Cancer Sci. 2008 Jan;99(1):129-39
references.pmid: 17949450
references.citation: Lancet Oncol. 2007 Jun;8(6):545-53
references.pmid: 17540306
references.citation: Cancer. 1983 Sep 15;52(6):974-7
references.pmid: 6683991
references.citation: Eur J Cancer. 2002 Mar;38(5):661-6
references.pmid: 11916548
references.citation: J Biol Chem. 2008 May 16;283(20):13799-805
references.pmid: 18353776
references.citation: EMBO Mol Med. 2013 Nov;5(11):1759-74
references.pmid: 24115572
references.citation: Mol Pharmacol. 2006 Jun;69(6):1879-90
references.pmid: 16543392
references.citation: Int J Cancer. 2007 Nov 1;121(9):1930-40
references.pmid: 17621631