Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, Shanxi, China.
Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
Molecules. 2019 Apr 7;24(7):1363. doi: 10.3390/molecules24071363.
Ponatinib is a multi-target protein tyrosine kinase inhibitor, and its effects on hepatocellular carcinoma cells have not been previously explored. In the present study, we investigated its effects on hepatocellular carcinoma cell growth and the underlying mechanisms. Toward SK-Hep-1 and SNU-423 cells, ponatinib induces apoptosis by upregulation of cleaved caspase-3 and -7 and promotes cell cycle arrest in the G1 phase by inhibiting CDK4/6/CyclinD1 complex and phosphorylation of retinoblastoma protein. It inhibits the growth-stimulating mitogen-activated protein (MAP) kinase pathway, the phosphorylation of Src on both negative and positive regulation sites, and Jak2 and Stat3 phosphorylation. Surprisingly, it also activates the PDK1, the protein kinase B (Akt), and the mechanistic target of rapamycin (mTOR) signaling pathway. Blocking mTOR signaling strongly sensitizes cells to inhibition by ponatinib and makes ponatinib a much more potent inhibitor of hepatocellular carcinoma cell proliferation. These findings demonstrate that ponatinib exerts both positive and negative effects on hepatocellular cell proliferation, and eliminating its growth-stimulating effects by drug combination or potentially by chemical medication can significantly improve its efficacy as an anti-cancer drug.
帕纳替尼是一种多靶点蛋白酪氨酸激酶抑制剂，其对肝癌细胞的作用尚未被探索。本研究旨在探讨帕纳替尼对肝癌细胞生长的影响及其作用机制。帕纳替尼可诱导 SK-Hep-1 和 SNU-423 细胞凋亡，通过上调 cleaved caspase-3 和 cleaved caspase-7 实现，同时通过抑制 CDK4/6/CyclinD1 复合物和视网膜母细胞瘤蛋白磷酸化，将细胞周期阻滞在 G1 期。它还抑制有丝分裂原激活的蛋白（MAP）激酶途径、Src 在负调控和正调控位点的磷酸化以及 Jak2 和 Stat3 的磷酸化。令人惊讶的是，它还激活 PDK1、蛋白激酶 B（Akt）和雷帕霉素靶蛋白（mTOR）信号通路。阻断 mTOR 信号通路可显著增强细胞对帕纳替尼的敏感性，使帕纳替尼成为一种更有效的肝癌细胞增殖抑制剂。这些发现表明，帕纳替尼对肝癌细胞增殖既有正性作用，也有负性作用，通过药物联合或潜在的化学药物治疗消除其促生长作用，可显著提高其作为抗癌药物的疗效。
