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Induction of cellular stress via the p38 MAPK pathway drives VELCADE® (bortezomib)‐induced apoptosis in esophageal squamous cell carcinoma cells
Author(s) -
Lioni Mercedes Ines,
Noma Kazuhiro,
Herlyn Meenhard,
Smalley Keiran
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1136.10
Subject(s) - bortezomib , apoptosis , cancer research , proteasome inhibitor , tunel assay , p38 mitogen activated protein kinases , proteasome , mapk/erk pathway , medicine , chemistry , kinase , biology , microbiology and biotechnology , multiple myeloma , biochemistry
Esophageal carcinoma is known to have a 5‐year survival rate of less than 20%. This shows a failure of current treatment regimens to provide patients with a significant life expectancy after diagnosis. In preliminary studies we used a novel three‐dimensional (3D) model, formed by esophageal squamous cell carcinoma (ESCC) cell aggregates embedded into collagen type I to allow growth and invasion within the 3D tissue like structure. Treatment with bortezomib, a proteasome inhibitor, was strongly growth inhibitory in both conventional and 3D settings. In a 3D reconstruction model of a primary esophageal tumor, TUNEL staining revealed the induction of apoptosis using 0.5uM of the drug. Induction of apoptosis proceeded through activation of caspase‐9 and ‐3, and was p53 independent. Animal experiments were performed using TE12 ESCC xenografts in NOD/SCID mice. Treated animals showed a bortezomib‐specific reduction of tumor size associated with decreased Ki67 staining and increased TUNEL positivity. Proteasome inhibitors are known to induce cellular stress. Treatment of the ESCC lines with bortezomib led to increased activity in both the p38 MAPK and JNK pathways. A role for p38 MAPK in bortezomib‐induced apoptosis was demonstrated by the ability of the p38 inhibitor SB230580 (10uM) to block the bortezomib‐induced cleavage of caspase‐3. Identical results were observed using selective knockdown of p38 MAPK using siRNA. Our investigation suggests that p38 MAPK induction could be a useful strategy for apoptosis induction when combined with bortezomib. Supported by the National Cancer Institute (grant P01‐CA098101)