Department of Pathology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Mol Cancer. 2009 Nov 10;8:99. doi: 10.1186/1476-4598-8-99.
Imatinib mesylate has significantly improved survival and quality of life of patients with gastrointestinal stromal tumors (GISTs). However, the molecular mechanism through which imatinib exerts its anti-tumor effects is not clear. Previously, we found up-regulation of insulin-like growth factor binding protein-3 (IGFBP3) expression in imatinib-responsive GIST cells and tumor samples. Because IGFBP3 regulates cell proliferation and survival and mediates the anti-tumor effects of a number of anti-cancer agents through both IGF-dependent and IGF-independent mechanisms, we hypothesized that IGFBP3 mediates GIST cell response to imatinib. To test this hypothesis, we manipulated IGFBP3 levels in two imatinib-responsive GIST cell lines and observed cell viability after drug treatment.
In the GIST882 cell line, imatinib treatment induced endogenous IGFBP3 expression, and IGFBP3 down-modulation by neutralization or RNA interference resulted in partial resistance to imatinib. In contrast, IGFBP3 overexpression in GIST-T1, which had no detectable endogenous IGFBP3 expression after imatinib, had no effect on imatinib-induced loss of viability. Furthermore, both the loss of IGFBP3 in GIST882 cells and the overexpression of IGFBP3 in GIST-T1 cells was cytotoxic, demonstrating that IGFBP3 has opposing effects on GIST cell viability.
This data demonstrates that IGFBP3 has dual, opposing roles in modulating GIST cell viability and response to imatinib in vitro. These preliminary findings suggest that there may be some clinical benefits to IGFBP3 therapy in GIST patients, but further studies are needed to better characterize the functions of IGFBP3 in GIST.
甲磺酸伊马替尼显著改善了胃肠道间质瘤（GIST）患者的生存和生活质量。然而，伊马替尼发挥其抗肿瘤作用的分子机制尚不清楚。以前，我们发现伊马替尼反应性 GIST 细胞和肿瘤样本中胰岛素样生长因子结合蛋白 3（IGFBP3）表达上调。因为 IGFBP3 通过 IGF 依赖和非依赖机制调节细胞增殖和存活，并介导许多抗癌药物的抗肿瘤作用，所以我们假设 IGFBP3 介导 GIST 细胞对伊马替尼的反应。为了验证这一假设，我们在两种伊马替尼反应性 GIST 细胞系中操纵 IGFBP3 水平，并观察药物治疗后细胞活力。
在 GIST882 细胞系中，伊马替尼治疗诱导内源性 IGFBP3 表达，中和或 RNA 干扰 IGFBP3 下调导致对伊马替尼的部分耐药。相比之下，在 GIST-T1 中，伊马替尼没有检测到内源性 IGFBP3 表达，IGFBP3 过表达对伊马替尼诱导的活力丧失没有影响。此外，GIST882 细胞中 IGFBP3 的缺失和 GIST-T1 细胞中 IGFBP3 的过表达均具有细胞毒性，表明 IGFBP3 对 GIST 细胞活力具有相反的影响。
这些数据表明，IGFBP3 在体外调节 GIST 细胞活力和对伊马替尼的反应中具有双重相反的作用。这些初步发现表明，IGFBP3 治疗 GIST 患者可能有一些临床益处，但需要进一步研究以更好地描述 IGFBP3 在 GIST 中的功能。
