Novel transketolase inhibitor oroxylin A suppresses the non-oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient-derived organoids.
Novel transketolase inhibitor oroxylin A suppresses the non-oxidative pentose phosphate pathway and hepatocellular carcinoma tumour growth in mice and patient-derived organoids.
复制标题
DOI：
10.1002/ctm2.1095
复制
发表时间：
2022-11
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Transketolase (TKT), a key rate‐limiting enzyme in the non‐oxidative branch of the pentose phosphate pathway (PPP), provides more than 85% of the ribose required for de novo nucleotide biosynthesis and promotes the development of hepatocellular carcinoma (HCC). Pharmacologic inhibition of TKT could impede HCC development and enhance treatment efficacy. However, no safe and effective TKT inhibitor has been approved. An online two‐dimensional TKT protein immobilised biochromatographic system was established for high‐throughput screening of TKT ligands. Oroxylin A was found to specifically bind TKT. Drug affinity responsive target stability, cellular thermal shift assay, surface plasmon resonance, molecular docking, competitive displacement assay, and site mutation were performed to identify the binding of oroxylin A with TKT. Antitumour effects of oroxylin A were evaluated in vitro, in human xenograft mice, diethylnitrosamine (DEN)‐induced HCC mice, and patient‐derived organoids (PDOs). Metabolomic analysis was applied to detect the enzyme activity. Transcriptome profiling was conducted to illustrate the anti‐HCC mechanism of oroxylin A. TKT knocking‐down HCC cell lines and PDOs were established to evaluate the role of TKT in oroxylin A‐induced HCC suppression. By targeting TKT, oroxylin A stabilised the protein to proteases and temperature extremes, decreased its activity and expression, resulted in accumulation of non‐oxidative PPP substrates, and activated p53 signalling. In addition, oroxylin A suppressed cell proliferation, induced apoptosis and cell‐cycle arrest, and inhibited the growth of human xenograft tumours and DEN‐induced HCC in mice. Crucially, TKT depletion exerted identical effects to oroxylin A, and the promising inhibitor also exhibited excellent therapeutic efficacy against clinically relevant HCC PDOs. These results uncover a unique role for oroxylin A in TKT inhibition, which directly targets TKT and suppresses the non‐oxidative PPP. Our findings will facilitate the development of small‐molecule inhibitors of TKT and novel therapeutics for HCC. Oroxylin A directly targets transketolase (TKT) to suppress the non‐oxidative pentose phosphate pathway and activate p53 signalling, leading to growth inhibition of hepatocellular carcinoma (HCC) cells, tumours, and patient‐derived tumour organoids. This will facilitate the development of small‐molecule inhibitors of TKT and novel therapeutics for HCC.
登录
查看更多内容
影响因子：
4.4
作者：
Coy, JF;Dubel, S;Poustka, A
通讯作者：
Poustka, A
影响因子：
5.6
作者：
Nauton，Lionel;Hecquet，Laurence;Thery，Vincent
通讯作者：
Thery，Vincent
DOI：
10.1016/j.bbrc.2018.03.083
发表时间：
2018-04-15
影响因子：
3.1
作者：
Cho JH;Kim GY;Mansfield BC;Chou JY
通讯作者：
Chou JY
影响因子：
5.8
作者：
Hertl, M;Cosimi, AB
通讯作者：
Cosimi, AB
影响因子：
4.6
作者：
Dai, Qinsheng;Yin, Qian;Lu, Na
通讯作者：
Lu, Na