Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells
Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells
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DOI：
10.1038/sj.bjc.6604003
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发表时间：
2007-10-16
影响因子：
8.8
通讯作者：
Ohyashiki, K.
中科院分区：
文献类型：
--
作者：
Hamamura, R. S.;Ohyashiki, J. H.;Ohyashiki, K.
成人T细胞白血病（ATL）是一种由htlv -i感染的T淋巴细胞引起的致死性肿瘤，通常表现为核因子κ B （nf - κ B）活化。尽管采用了多种治疗方案，但ATL的预后较差，迫切需要新的治疗策略。因此，我们探索了蛋白酶体抑制剂硼替佐米在ATL细胞中的作用和分子机制。我们发现硼替佐米诱导细胞死亡，并且硼替佐米通过在三种ATL细胞系（TaY、MT-2和MT-4）中稳定I-kappa B抑制了组成型NF-kB的激活。TaY细胞的寡核苷酸DNA芯片分析显示，编码热休克蛋白的基因（HSPAIA、STIP I、HSPA IB和HSPCA）、蛋白质折叠相关基因（CDC37和ANAPC5）、fas相关因子I （FAF I）和氧化应激相关基因血红素加氧酶I （HMOX- I）上调，该基因已知是缺氧诱导基因I α (HIF-I α)的靶基因。在药理学有效剂量的硼替佐米存在下，原卟啉钴诱导HMOX- I而不是HIF-I α表达，并增加硼替佐米诱导的细胞凋亡。相比之下，原卟啉锌下调HMOX-I的表达，从而部分抑制硼替佐米诱导的细胞死亡。这表明hmox - 1可能调节硼替佐米对ATL细胞的抗癌作用，可能成为治疗ATL患者的分子靶点。
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.