Basic Medical Institute; Hongqiao International Institute of Medicine, Tongren Hospital; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
Theranostics. 2021 Apr 3;11(12):6006-6018. doi: 10.7150/thno.59841. eCollection 2021.
: Sorafenib is the only FDA-approved first-line target drug for HCC patients. However, sorafenib merely confers 3-5 months of survival benefit with less than 30% of HCC patients sensitive to sorafenib therapy. Thus, it's necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. : The principal component analysis, gene ontology, and KEGG analysis are utilized following RNA-sequencing. The mass spectrometry analysis following immunoprecipitation is performed to discover the phosphatase targets. Most importantly, both the cell line-derived xenograft (CDX) and the patient-derived xenograft (PDX) mouse model are used to determine the effect of 3-HAA on sorafenib-resistant HCC . : In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib or 3-HAA alone. When used in combination, the treatment particularly prevents the xenograft from growing. Combined treatment also suppresses the growth of sorafenib-resistant (≥30mg/kg) PDXs. In a set of mechanistic experiments, we find enhanced AKT activation and decreased apoptotic cells in and acquired sorafenib-resistant HCC cells and tissues. 3-HAA decreases AKT phosphorylation and increases the apoptosis of HCC in both cultured cells and mouse xenografts by upregulation of phosphatases PPP1R15A/DUSP6. PPP1R15A/PPP1α directly reduces Akt phosphorylation while DUSP6 decreases Akt activity through inhibiting PDK1. The AKT activator abolishes 3-HAA inhibition of HCC growth and in mice. : This study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by upregulation of phosphatases, suggesting it as a promising molecule for HCC therapy.
索拉非尼是唯一获得 FDA 批准的用于 HCC 患者的一线靶向药物。然而，索拉非尼仅能为 HCC 患者提供 3-5 个月的生存获益，并且仅有不到 30%的 HCC 患者对索拉非尼治疗敏感。因此，有必要开发一种能够增加 HCC 对索拉非尼敏感性的增敏剂。
在 RNA 测序后进行主成分分析、基因本体论和 KEGG 分析。通过免疫沉淀后的质谱分析来发现磷酸酶靶点。最重要的是，我们使用细胞系衍生的异种移植（CDX）和患者衍生的异种移植（PDX）小鼠模型来确定 3-HAA 对索拉非尼耐药 HCC 的作用。
在携带 HCC 异种移植的裸鼠中，索拉非尼或 3-HAA 单独治疗均可抑制肿瘤生长。联合治疗时，特别能阻止异种移植生长。联合治疗还抑制了索拉非尼耐药（≥30mg/kg）PDX 的生长。在一组机制实验中，我们发现增强的 AKT 激活和减少的凋亡细胞在 HCC 细胞和组织中。3-HAA 通过上调磷酸酶 PPP1R15A/DUSP6 降低 AKT 磷酸化并增加 HCC 的凋亡，在培养细胞和小鼠异种移植中均如此。PPP1R15A/PPP1α 直接降低 Akt 磷酸化，而 DUSP6 通过抑制 PDK1 降低 Akt 活性。AKT 激活剂消除了 3-HAA 对 HCC 生长的抑制作用。
这项研究表明，3-HAA 通过上调磷酸酶使 HCC 细胞对索拉非尼敏感，提示它是一种有前途的 HCC 治疗分子。
