Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India.
Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
Biochem Biophys Res Commun. 2020 Nov 19;532(4):570-575. doi: 10.1016/j.bbrc.2020.08.068. Epub 2020 Sep 6.
Hepatocellular cancer (HCC) is one of the leading causes of mortality worldwide. Unfortunately, a limited choice of anti-cancer drugs is available for treatment, owing to their minimal efficacy and development of acquired resistance. Autophagy, a cellular survival pathway, often exhibits a pleiotropic role in HCC progression. Studies show increased autophagy in established HCC, promoting the survival of HCC cells in the tumour microenvironment. Therefore, novel anti-autophagy drugs hold promise for preventing HCC progression. Here, using a non-biased transcriptomics analysis in HepG2 cells we demonstrate the existence of an autophagy-FOXM1 nexus regulating growth in HepG2 cells. Additionally, we show that suppression of autophagy by an Unc-51 Like Autophagy Activating Kinase 1(ULK1) inhibitor not only attenuates the expression of FOXM1 and its transcriptional targets, but also has a synergistic effect on the inhibition of HepG2 growth when combined with FOXM1 inhibitors. Thus, the autophagic protein, ULK1, is a promising candidate for preventing HCC progression. Collectively, our results provide new insight into the role of autophagy in HCC growth and are a proof-of concept for combinatorial therapy using ULK1 and FOXM1 inhibitors.
肝细胞癌（HCC）是全球主要的死亡原因之一。不幸的是，由于其疗效有限和获得性耐药，可用于治疗的抗癌药物选择有限。自噬是一种细胞存活途径，在 HCC 进展中常表现出多效性作用。研究表明，在已建立的 HCC 中自噬增加，促进 HCC 细胞在肿瘤微环境中的存活。因此，新型抗自噬药物有望预防 HCC 进展。在这里，我们使用 HepG2 细胞中的无偏转录组学分析，证明了自噬-FOXM1 连接在调节 HepG2 细胞生长中的存在。此外，我们还表明，通过 Unc-51 样自噬激活激酶 1（ULK1）抑制剂抑制自噬，不仅会减弱 FOXM1 及其转录靶标的表达，而且当与 FOXM1 抑制剂联合使用时，对 HepG2 生长的抑制也具有协同作用。因此，自噬蛋白 ULK1 是预防 HCC 进展的有前途的候选物。总之，我们的研究结果为自噬在 HCC 生长中的作用提供了新的见解，并为使用 ULK1 和 FOXM1 抑制剂进行联合治疗提供了概念验证。
