Chemistry & Biology, Nucleo(s)tides & Immunology for Therapy (CBNIT), CNRS UMR8601, Université Paris Descartes, PRES Sorbonne Paris Cité, UFR Biomédicale, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 25 rue de Dr Roux, 75724 Paris, France.
Cancer Lett. 2015 Apr 28;360(1):48-59. doi: 10.1016/j.canlet.2015.02.016. Epub 2015 Feb 12.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是最有前途的实验性癌症治疗药物之一，目前正在临床试验中进行测试。然而，人癌细胞对 TRAIL 诱导的凋亡的内在和获得性耐药性在建立临床上有效的 TRAIL 治疗方面构成了一个巨大的问题。为了评估 TRAIL 耐药性在人胰腺癌细胞中的调节作用，我们研究了 TRAIL 耐药的胰腺细胞系 PANC-1。我们发现，与 TRAIL 联合使用新型粘着斑激酶（FAK）抑制剂 PH11 可迅速诱导 TRAIL 耐药的 PANC-1 细胞凋亡，但对正常的人成纤维细胞没有作用。为了解释这种增敏作用，我们发现 PH11 通过抑制 FAK 和磷脂酰肌醇-3 激酶（PI3K）/AKT 途径下调 c-FLIP，从而恢复 PANC-1 细胞中的 TRAIL 凋亡途径。这些发现表明，这种联合治疗可能为安全有效地治疗胰腺癌提供一种有吸引力的治疗策略。
