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O'Callaghan C, Fanning LJ, Barry OP
Anti-cancer drugs
p38d MAPK phenotype: an indicator of chemotherapeutic response in oesophageal squamous cell carcinoma.
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We recently documented p38d differential expression and function in oesophageal squamous cell carcinoma (OESCC). This study expands upon these findings and investigates whether p38d 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). p38d-positive and p38d-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. p38d-negative OESCC is less sensitive to standard CF chemotherapy compared with p38d-positive cells. However, following ACF treatment p38d-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 (żżm) 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. p38d-negative OESCC is more resistant to traditional CF treatment compared with p38d-positive OESCC. In light of these results, p38d phenotyping of tumour tissue may be of considerable value in deciding on an optimal therapeutic strategy for patients with p38d-negative OESCC.This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially.
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