Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway.
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 G2-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 of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.
Lioni
Mercedes
M
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Noma
Kazuhiro
K
Snyder
Andrew
A
Klein-Szanto
Andres
A
Diehl
J Alan
JA
Rustgi
Anil K
AK
Herlyn
Meenhard
M
Smalley
Keiran S M
KS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology* / Q000532:radiotherapy; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology* / Q000532:radiotherapy; D016195:G2 Phase / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008938:Mitosis / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000201:enzymology; D011719:Pyrazines / Q000494:pharmacology*; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D001897:Boronic Acids; C468783:H2AX protein, human; D006657:Histones; D011719:Pyrazines; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3
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