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-I-infected T lymphocytes frequently exhibiting nuclear factor-kappa B (NF-kappa B) 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-kB activation via I-kappa B 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 (HSPAIA, STIP I, HSPA IB, and HSPCA), genes related to protein folding (CDC37 and ANAPC5), Fas-associated factor I (FAF I) and an oxidative stress-related gene, heme oxygenase-I (HMOX- I), known to be a target gene of hypoxia-inducible gene-I alpha (HIF-I alpha). Cobalt protoporphyrin induced HMOX- I, instead of HIF-I alpha expression and increased bortezomib-induced apoptosis in the presence of pharmacologically effective doses of bortezomib. In contrast, zinc protoporphyrin downregulated HMOX-I expression, thereby partially inhibiting bortezomib-induced cell death. This indicates that HMOX-I may modulate anticancer effects of bortezomib in ATL cells, and could be a molecular target in treating ATL patients.