Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells.
Adult T-cell leukaemia (ATL) is a lethal neoplasia derived from HTLV-1-infected T lymphocytes frequently exhibiting nuclear factor-kappaB (NF-kappaB) activation. Despite the use of various treatment regimens, the prognosis of ATL is poor, and new treatment strategies are urgently needed. We therefore explored the effect and the molecular mechanism of a proteasome inhibitor, bortezomib, in ATL cells. We found bortezomib-induced cell death, and bortezomib suppressed constitutive NF-kappaB activation via I-kappaB stabilisation in three ATL cell lines (TaY, MT-2 and MT-4). An oligonucleotide DNA microarray analysis of TaY cells revealed upregulation of genes encoding heat shock proteins (HSPA1A, STIP1, HSPA1B, and HSPCA), genes related to protein folding (CDC37 and ANAPC5), Fas-associated factor 1(FAF1) and an oxidative stress-related gene, heme oxygenase-1(HMOX-1), known to be a target gene of hypoxia-inducible gene-1 alpha (HIF-1 alpha). Cobalt protoporphyrin induced HMOX-1, instead of HIF-1 alpha expression and increased bortezomib-induced apoptosis in the presence of pharmacologically effective doses of bortezomib. In contrast, zinc protoporphyrin downregulated HMOX-1 expression, thereby partially inhibiting bortezomib-induced cell death. This indicates that HMOX-1 may modulate anticancer effects of bortezomib in ATL cells, and could be a molecular target in treating ATL patients.
Hamamura
R S
RS
Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.
Ohyashiki
J H
JH
Kurashina
R
R
Kobayashi
C
C
Zhang
Y
Y
Takaku
T
T
Ohyashiki
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011524:Protoporphyrins / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001897:Boronic Acids; D020672:I-kappa B Proteins; D016328:NF-kappa B; D011524:Protoporphyrins; D011719:Pyrazines; C007095:cobaltiprotoporphyrin; D000069286:Bortezomib; D051547:Heme Oxygenase-1