Shi Yijiang, Gera Joseph, Hsu Jung-Hsin, Van Ness Brian, Lichtenstein Alan
Hematology-Oncology Division of the West Los Angeles VA-UCLA Medical Center, Los Angeles, California 90073, USA.
Mol Cancer Ther. 2003 Jun;2(6):563-72.
Farnesyl transferase inhibitors (FTIs) are anticancer agents designed to target ras processing and ras-dependent signal pathways. Because oncogenic ras mutations are found in up to 50% of multiple myeloma (MM) specimens, these agents may be effective in this disease. However, some preclinical studies suggest that FTI antitumor responses are unrelated to effects on ras. To address this issue in myeloma, we used the ANBL-6 myeloma cell line where interleukin (IL)-6-dependent cells are stably transfected with mutated N-ras or K-ras genes. Because expression of mutated ras allows for IL-6-independent growth, this is a good model to test whether FTIs specifically target growth-promoting ras-activated pathways in myeloma. Although they had little effect in 10% serum, two separate FTIs induced apoptosis of myeloma cells when cultured in low serum, and mutated ras-expressing cells were more sensitive than wild-type (WT) ras-expressing cells. However, induction of apoptosis did not correlate with inhibition of ras processing. Although they had no effect on AKT activity, under low serum conditions FTIs inhibited constitutive activation of the p70S6kinase and nuclear factor kappaB signal proteins in both mutated ras-expressing MM lines and extracellular signal-regulated kinase (ERK) activity in mutated N-ras-expressing cells. However, in studies where p70, nuclear factor kappaB, and ERK were comparably inhibited by other inhibitors or by gene transfer, we could not identify effects on these pathways as participating in the apoptotic response. FTIs were also able to abrogate the IL-6 proliferative response of WT ras-expressing MM cells, and this was associated with inhibition of IL-6-induced activation of ERK, AKT, and p70. The induction of apoptosis and prevention of the IL-6 response in MM cells containing mutated or WT ras provide support for the therapeutic potential of FTIs in this disease.
法尼基转移酶抑制剂（FTIs）是一类旨在靶向Ras加工过程和Ras依赖性信号通路的抗癌药物。由于在高达50%的多发性骨髓瘤（MM）标本中发现了致癌性Ras突变，这些药物可能对这种疾病有效。然而，一些临床前研究表明，FTIs的抗肿瘤反应与对Ras的作用无关。为了解决骨髓瘤中的这个问题，我们使用了ANBL-6骨髓瘤细胞系，其中依赖白细胞介素（IL）-6的细胞被稳定转染了突变的N-Ras或K-Ras基因。由于突变Ras的表达允许细胞在不依赖IL-6的情况下生长，这是一个很好的模型，用于测试FTIs是否特异性靶向骨髓瘤中促进生长的Ras激活通路。尽管它们在10%血清中作用很小，但两种不同的FTIs在低血清培养时可诱导骨髓瘤细胞凋亡，且表达突变Ras的细胞比表达野生型（WT）Ras的细胞更敏感。然而，凋亡的诱导与Ras加工的抑制无关。尽管它们对AKT活性没有影响，但在低血清条件下，FTIs抑制了表达突变Ras的MM细胞系中p70S6激酶和核因子κB信号蛋白的组成性激活，以及表达突变N-Ras的细胞中的细胞外信号调节激酶（ERK）活性。然而，在使用其他抑制剂或基因转移使p70、核因子κB和ERK受到同等抑制的研究中，我们无法确定这些通路的抑制参与了凋亡反应。FTIs还能够消除表达WT Ras的MM细胞的IL-6增殖反应，这与抑制IL-6诱导的ERK、AKT和p70激活有关。在含有突变或WT Ras的MM细胞中诱导凋亡和预防IL-6反应，为FTIs在这种疾病中的治疗潜力提供了支持。
