PMID- 28726775
OWN - NLM
STAT- MEDLINE
DCOM- 20180405
LR  - 20231213
IS  - 2041-4889 (Electronic)
VI  - 8
IP  - 7
DP  - 2017 Jul 20
TI  - Oroxylin A activates PKM1/HNF4 alpha to induce hepatoma differentiation and block 
      cancer progression.
PG  - e2944
LID - 10.1038/cddis.2017.335 [doi]
AB  - 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-4alpha (hepatocyte nuclear factor 4 alpha) directly, promoting the transcription 
      of HNF-4alpha-targeted genes. This work suggested that OA increased PKM1/PKM2 ratio, 
      resulting in HNF-4alpha 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.
FAU - Wei, Libin
AU  - Wei L
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Dai, Yuanyuan
AU  - Dai Y
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Zhou, Yuxin
AU  - Zhou Y
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - He, Zihao
AU  - He Z
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Yao, Jingyue
AU  - Yao J
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Zhao, Li
AU  - Zhao L
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Guo, Qinglong
AU  - Guo Q
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
FAU - Yang, Lin
AU  - Yang L
AD  - State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of 
      Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, 
      China Pharmaceutical University, Nanjing, 24 Tongjiaxiang, People's Republic of 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170720
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Carrier Proteins)
RN  - 0 (Flavonoids)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Membrane Proteins)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Thyroid Hormones)
RN  - 53K24Z586G (5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one)
SB  - IM
MH  - Carcinoma, Hepatocellular/*drug therapy/genetics/metabolism/pathology
MH  - Carrier Proteins/genetics/*metabolism
MH  - Cell Differentiation/*drug effects/genetics
MH  - Flavonoids/*pharmacology
MH  - Hep G2 Cells
MH  - Hepatocyte Nuclear Factor 4/genetics/*metabolism
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Membrane Proteins/genetics/*metabolism
MH  - Neoplasm Proteins/genetics/*metabolism
MH  - Thyroid Hormones/genetics/*metabolism
MH  - Thyroid Hormone-Binding Proteins
PMC - PMC5550876
COIS- The authors declare no conflict of interest.
EDAT- 2017/07/21 06:00
MHDA- 2018/04/06 06:00
PMCR- 2017/07/01
CRDT- 2017/07/21 06:00
PHST- 2017/02/16 00:00 [received]
PHST- 2017/05/15 00:00 [revised]
PHST- 2017/06/08 00:00 [accepted]
PHST- 2017/07/21 06:00 [entrez]
PHST- 2017/07/21 06:00 [pubmed]
PHST- 2018/04/06 06:00 [medline]
PHST- 2017/07/01 00:00 [pmc-release]
AID - cddis2017335 [pii]
AID - 10.1038/cddis.2017.335 [doi]
PST - epublish
SO  - Cell Death Dis. 2017 Jul 20;8(7):e2944. doi: 10.1038/cddis.2017.335.