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Lioni M, Noma K, Snyder A, Klein-Szanto A, Diehl JA, Rustgi AK, Herlyn M, Smalley KS
Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway
Molecular Cancer Therapeutics (2008) 7:2866-2875.
Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate < 5%. From an initial drug screen, we identified bortezomib as having robust activity in ESCC lines. Mechanistically, bortezomib induced a G(2)-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation !
Publication Date: 2008-09-01.
Last updated on Sunday, July 12, 2020