Department of Translational Pharmacology, Consorzio Mario Negri Sud, S, Maria Imbaro, Italy.
Mol Cancer. 2013 Aug 6;12(1):88. doi: 10.1186/1476-4598-12-88.
Farnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity.
Using FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses.
ABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells.
Our data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.
法尼基转移酶抑制剂（FTIs）是一种抗癌药物，在依赖 Ras 和不依赖 Ras 的肿瘤细胞和异种移植模型中具有广泛的活性。由于潜在的 FTase 靶点众多，因此，FTI 抑制蛋白法尼基化如何导致癌细胞增殖减少的机制仍不清楚。FTIs 的低毒性和口服可用性促使它们被引入临床试验，用于治疗乳腺癌、血液恶性肿瘤、晚期实体瘤和胰腺癌，以及 Hutchinson-Gilford 早老综合征。尽管它们在与髓样恶性肿瘤和实体瘤的常规抗癌治疗联合治疗中的疗效有很大的希望，但临床试验的总体结果远低于预期。FTIs 在临床上的进一步开发将强烈依赖于了解这些药物如何影响细胞的整体活性。
我们使用法尼基转移酶抑制剂 I 和酵母基因敲除库的全基因组化学筛选，鉴定了那些失活会增加这种 FTI 肽模拟物的抗增殖作用的基因。在一系列癌细胞系中，使用 FTI-277 进行增殖和生化测定，并通过基于多参数的图像分析进行平行分析，验证了主要发现。
ABC 转运蛋白 Pdr10 或 p-21 激活激酶（PAK）基因的缺失会增加 FTI 抑制剂 I 在酵母细胞中的抗增殖作用。与此一致的是，在黑色素瘤（A375MM）、肺（A549）和结肠（HT29）细胞中，使用 IPA3 联合 FTI-277 抑制 I 组 PAK 会增强细胞增殖的抑制作用，但在上皮细胞（HeLa）或乳腺癌（MCF7）细胞中则没有。FTI-277 处理后，HeLa 和 A375MM 细胞中 I 组 PAK 的核定位均发生变化，但仅在 HeLa 细胞中观察到 PAK 蛋白水平的上调。
我们的数据支持这样一种观点，即 I 组 PAK 是 FTI 治疗激活的生存途径的一部分，抑制 I 组 PAK 可增强 FTI 在酵母和癌细胞中的抗增殖作用。这些发现为 FTI 与 PAK 抑制剂联合应用于黑色素瘤、肺癌和结肠癌提供了新的策略。
