Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells.
Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells.
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DOI：
10.1111/j.1582-4934.2009.00795.x
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发表时间：
2010-06
影响因子：
5.3
通讯作者：
Amin HM
中科院分区：
文献类型：
--
作者：
Shi P;Chandra J;Sun X;Gergely M;Cortes JE;Garcia-Manero G;Arlinghaus RB;Lai R;Amin HM
尽管通过 I 型胰岛素样生长因子受体 (IGF-IR) 的信号传导维持造血细胞的存活，但 IGF-IR 在血液肿瘤中的具体作用仍然很大程度上未知。慢性粒细胞白血病（CML）是慢性骨髓增殖性疾病最常见的亚型。通常，CML 发展为慢性期 (CP) 疾病，并进展为加速期 (AP) 和急变期 (BP)。在这项研究中，我们证明 IGF-IR 在四种 CML 细胞系中普遍表达。 IGF-IR在CP和AP患者中分别仅表达30%和25%，但其表达频率在BP患者中增加至73%。定量实时 PCR 证实了随着 CML 进展，IGF-IR 表达水平增加，该结果表明 BP 患者中 IGF-IR mRNA 水平显着升高。 IGF-IR 的抑制降低了 CML 细胞系的活力和增殖，并抑制了它们在软琼脂中的生长。重要的是，抑制 IGF-IR 降低了对甲磺酸伊马替尼耐药的细胞的活力，包括用 p210 BCR-ABL 突变体转染的 BaF3 细胞、CML 细胞系和来自患者的原发性肿瘤细胞。抑制 IGF-IR 的负面影响可归因于下游靶蛋白改变导致的细胞凋亡和细胞周期停滞。我们的研究结果表明，IGF-IR 可能代表一个潜在的分子靶标，特别是对于晚期或伊马替尼耐药病例。
Although signalling through the type I insulin-like growth factor receptor (IGF-IR) maintains the survival of haematopoietic cells, a specific role of IGF-IR in haematological neoplasms remains largely unknown. Chronic myeloid leukaemia (CML) is the most common subtype of chronic myeloproliferative diseases. Typically, CML evolves as a chronic phase (CP) disease that progresses into accelerated (AP) and blast phase (BP) stages. In this study, we show that IGF-IR is universally expressed in four CML cell lines. IGF-IR was expressed in only 30% and 25% of CP and AP patients, respectively, but its frequency of expression increased to 73% of BP patients. Increased expression levels of IGF-IR with CML progression was supported by quantitative real-time PCR that demonstrated significantly higher levels of IGF-IR mRNA in BP patients. Inhibition of IGF-IR decreased the viability and proliferation of CML cell lines and abrogated their growth in soft agar. Importantly, inhibition of IGF-IR decreased the viability of cells resistant to imatinib mesylate including BaF3 cells transfected with p210 BCR-ABL mutants, CML cell lines and primary neoplastic cells from patients. The negative effects of inhibition of IGF-IR were attributable to apoptosis and cell cycle arrest due to alterations of downstream target proteins. Our findings suggest that IGF-IR could represent a potential molecular target particularly for advanced stage or imatinib-resistant cases.
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影响因子：
4.8
作者：
Mauro, L;Bartucci, M;Surmacz, E
通讯作者：
Surmacz, E
影响因子：
7.3
作者：
Amin, H. M.;Hoshino, K.;Garcia-Manero, G.
通讯作者：
Garcia-Manero, G.
影响因子：
5.3
作者：
Martin, MJ;Melnyk, N;Sorensen, PHB
通讯作者：
Sorensen, PHB
影响因子：
20.3
作者：
Ban, Kechen;Gao, Yin;Chandra, Joya
通讯作者：
Chandra, Joya
影响因子：
8
作者：
Lakshmikuttyamma, A.;Pastural, E.;Geyer, C. R.
通讯作者：
Geyer, C. R.