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Abstract：
Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation, such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and the results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed additive effects of the dual inhibition of the two pathways, in accordance with the inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies.
摘要：
胆管细胞癌（CCA）是第二常见的原发性肝癌，随着全球发病率的增加和治疗选择的不足。肝内和肝外胆管有明显不同的胚胎起源和发育行为，因此，肝内和肝外CCA（ICC与ECC)在分子上是不同的。肿瘤治疗中一个有希望的策略是靶向治疗，靶向调节细胞存活和增殖的蛋白质，如MAPK/ERK和PI3K/AKT/mTOR信号通路。先前已经在CCA细胞系中测试了这些途径的抑制剂。然而,这些细胞系不能明确地分配给ICC或ECC，结果表明，通过靶向治疗诱导细胞凋亡。我们测试了靶向疗法（司米替尼，MK2206）在三种定义的ICC细胞系（HuH28，RBE，SSP25)。我们观察到两种途径双重抑制的累加效应，根据抑制磷酸-AKT和磷酸-ERK1/2的表达。双重抑制比每个单一抑制更有效地阻断增殖，但细胞数量没有下降到基线以下。因此，我们观察到G1期停滞，但未观察到细胞凋亡或细胞死亡（通过裂解的caspase-3，AIFM1调节，次G0/G1阶段）。我们得出的结论是，MAPK/ERK和PI3K/AKT/mTOR通路的双重抑制对体外阻断ICC细胞系的增殖非常有效；然而，必须严格检查潜在的临床应用，作为增殖阻滞也可以诱导对标准疗法的抗性。
