Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression.
Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block cancer progression.
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Oroxylin A 激活 PKM1/HNF4 α 诱导肝癌分化并阻止癌症进展
DOI：
10.1038/cddis.2017.335
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发表时间：
2017-07-20
影响因子：
9
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Wei L;Dai Y;Zhou Y;He Z;Yao J;Zhao L;Guo Q;Yang L
肝癌是世界范围内癌症死亡的第二大原因，没有有效的治疗。传统的肝癌化疗对患者有很大的副作用，而靶向药物，如索拉非尼，通常存在耐药性。木脂素A（OA）是黄芪中主要的生物活性黄酮类化合物，具有较强的抗肝癌作用，但对正常组织的毒性较低。迄今为止，还没有分化诱导剂对实体瘤发挥疗效的报道。本研究结果表明，OA通过诱导高PKM 1/PKM 2比值抑制肝癌细胞的增殖和诱导分化。OA抑制多聚嘧啶链结合蛋白的表达，导致PKM 2的减少和PKM 1的增加。进一步的研究表明，PKM 1的表达增加后，PKM 1转位到细胞核内，直接与HNF-4α（hepatocyte nuclear factor 4 alpha）结合，促进HNF-4α靶向基因的转录。本研究表明OA增加PKM 1/PKM 2比值，导致HNF-4α活化和肝癌分化。特别是OA对人原发性肝癌细胞和肝癌患者源性肿瘤异种移植模型均显示出可靠的抗肿瘤作用，并减缓了原发性肝癌的发展，提示OA可开发成为一种新型的肝癌诱导分化剂。
Liver cancer is the second cause of death from cancer worldwide, without effective treatment. Traditional chemotherapy for liver cancer has big side effects for patients, whereas targeted drugs, such as sorafenib, commonly have drug resistance. Oroxylin A (OA) is the main bioactive flavonoids of Scutellariae radix, which has strong anti-hepatoma effect but low toxicity to normal tissue. To date, no differentiation-inducing agents have been reported to exert a curative effect on solid tumors. Here our results demonstrated that OA restrained the proliferation and induced differentiation of hepatoma both in vitro and in vivo, via inducing a high PKM1 (pyruvate kinase M1)/PKM2 (pyruvate kinase M2) ratio. In addition, inhibited expression of polypyrimidine tract-binding protein by OA was in charge of the decrease of PKM2 and increase of PKM1. Further studies demonstrated that increased PKM1 translocated into the nucleus and bound with HNF-4α (hepatocyte nuclear factor 4 alpha) directly, promoting the transcription of HNF-4α-targeted genes. This work suggested that OA increased PKM1/PKM2 ratio, resulting in HNF-4α activation and hepatoma differentiation. Especially, OA showed reliable anticancer effect on both human primary hepatocellular carcinoma cells and patient-derived tumor xenograft model for hepatoma, and slowed down the development of primary hepatoma, suggesting that OA could be developed into a novel differentiation inducer agent for hepatoma.
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DOI：
10.1111/j.1478-3231.2008.01957.x
发表时间：
2009-04
期刊：
Liver international : official journal of the International Association for the Study of the Liver
影响因子：
--
作者：
Tandon P;Garcia-Tsao G
通讯作者：
Garcia-Tsao G
影响因子：
25.7
作者：
Toyoda, Hidenori;Kumada, Takashi;Maeda, Atsuyuki
通讯作者：
Maeda, Atsuyuki
影响因子：
2.7
作者：
Martínez-Jiménez, CP;Jover, R;Castell, JV
通讯作者：
Castell, JV
影响因子：
64.8
作者：
Saha, Supriya K.;Parachoniak, Christine A.;Ghanta, Krishna S.;Fitamant, Julien;Ross, Kenneth N.;Najem, Mortada S.;Gurumurthy, Sushma;Akbay, Esra A.;Sia, Daniela;Cornella, Helena;Miltiadous, Oriana;Walesky, Chad;Deshpande, Vikram;Zhu, Andrew X.;Hezel, Aram F.;Yen, Katharine E.;Straley, Kimberly S.;Travins, Jeremy;Popovici-Muller, Janeta;Gliser, Camelia;Ferrone, Cristina R.;Apte, Udayan;Llovet, Josep M.;Wong, Kwok-Kin;Ramaswamy, Sridhar;Bardeesy, Nabeel
通讯作者：
Bardeesy, Nabeel
影响因子：
3.2
作者：
DOMINGO, M;EINIG, C;REINACHER, M
通讯作者：
REINACHER, M