Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.
Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although >85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non-chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-kappaB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors.
Bauer
Sebastian
S
Sarcoma Center, West German Cancer Center, University of Essen Medical School, Essen, Germany.
Parry
Joshua A
JA
Mühlenberg
Thomas
T
Brown
Matthew F
MF
Seneviratne
Danushka
D
Chatterjee
Payel
P
Chin
Anna
A
Rubin
Brian P
BP
Kuan
Shih-Fan
SF
Fletcher
Jonathan A
JA
Duensing
Stefan
S
Duensing
Anette
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D001897:Boronic Acids; C468783:H2AX protein, human; D006657:Histones; D011719:Pyrazines; D000069286:Bortezomib; D019009:Proto-Oncogene Proteins c-kit