PMID- 30841449
OWN - NLM
STAT- MEDLINE
DCOM- 20190621
LR  - 20190621
IS  - 1950-6007 (Electronic)
IS  - 0753-3322 (Linking)
VI  - 111
DP  - 2019 Mar
TI  - 6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK 
      activation and metabolic reprogramming.
PG  - 1353-1358
LID - S0753-3322(18)35443-X [pii]
LID - 10.1016/j.biopha.2019.01.028 [doi]
AB  - Better understanding of the molecular mechanism involved in hepatocellular 
      carcinoma (HCC) progression is essential for the development of therapeutic 
      strategies to overcome chemoresistance in HCC patients. In this work, we show 
      that 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative 
      pentose phosphate pathway, is important for HCC growth and survival. Compared to 
      normal liver tissues, we demonstrate that 6PGD expression is upregulated in HCC 
      tissues. 6PGD overexpression increases 6PGD activity and promotes growth in 
      normal liver cells. In contrast, targeting 6PGD using both genetic and 
      pharmacological approaches inhibits HCC growth and survival. Combination of 
      chemotherapeutic agents with 6PGD inhibition achieves greater efficacy in 
      inhibiting HCC growth and survival than chemotherapeutic agent alone. We further 
      show that inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and 
      acetyl-coenzyme A carboxylase 1 (ACC1), and decreases level of NADPH/NAD + and 
      NADH in HCC, leading to SIRT1 activity reduction and oxidative stress. 
      Conversely, AMPK depletion significantly abolishes the effects of physcion (a 
      selective small-molecule 6PGD inhibitor) in decreasing NADPH/NAD + ratio, growth 
      and survival, confirming the role of AMPK as the relevant upstream activator with 
      6PGD inhibition in HCC cells. Our work is the first to demonstrate the 
      upregulation of 6PGD and its critical involvement in growth and survival in HCC. 
      Our findings suggest 6PGD as a promising therapeutic target to overcome 
      chemoresistance in HCC.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier Masson SAS.. All rights 
      reserved.
FAU - Chen, Hu
AU  - Chen H
AD  - Department of Hepatobiliary and Pancreatic Surgery, Hubei Cancer Hospital, Tongji 
      Medical College, Huazhong University of Science Technology, Wuhan, China.
FAU - Wu, Dongde
AU  - Wu D
AD  - Department of Hepatobiliary and Pancreatic Surgery, Hubei Cancer Hospital, Tongji 
      Medical College, Huazhong University of Science Technology, Wuhan, China.
FAU - Bao, Lequn
AU  - Bao L
AD  - Department of Hepatobiliary and Pancreatic Surgery, Hubei Cancer Hospital, Tongji 
      Medical College, Huazhong University of Science Technology, Wuhan, China.
FAU - Yin, Tao
AU  - Yin T
AD  - Department of Hepatobiliary and Pancreatic Surgery, Hubei Cancer Hospital, Tongji 
      Medical College, Huazhong University of Science Technology, Wuhan, China.
FAU - Lei, Dansheng
AU  - Lei D
AD  - Department of Medical Laboratory, Hubei Cancer Hospital, Tongji Medical College, 
      Huazhong University of Science Technology, Wuhan, China.
FAU - Yu, Jing
AU  - Yu J
AD  - Department of Medical Laboratory, Hubei Cancer Hospital, Tongji Medical College, 
      Huazhong University of Science Technology, Wuhan, China.
FAU - Tong, Xianli
AU  - Tong X
AD  - Department of Medical Laboratory, Hubei Cancer Hospital, Tongji Medical College, 
      Huazhong University of Science Technology, Wuhan, China. Electronic address: 
      jenny.tongtong@163.com.
LA  - eng
PT  - Journal Article
DEP - 20190117
PL  - France
TA  - Biomed Pharmacother
JT  - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
JID - 8213295
RN  - 0 (Antineoplastic Agents)
RN  - 53-59-8 (NADP)
RN  - EC 1.1.1.43 (Phosphogluconate Dehydrogenase)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Acetyl-CoA Carboxylase/metabolism
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Hepatocellular/*drug therapy/*metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/*metabolism
MH  - NADP/metabolism
MH  - Oxidation-Reduction/drug effects
MH  - Oxidative Stress/drug effects
MH  - Pentose Phosphate Pathway/drug effects
MH  - Phosphogluconate Dehydrogenase/*antagonists & inhibitors
MH  - Sirtuin 1/metabolism
MH  - Up-Regulation/drug effects
OTO - NOTNLM
OT  - 6PGD
OT  - AMPK
OT  - HCC chemoresistance
OT  - NADPH metabolism
EDAT- 2019/03/08 06:00
MHDA- 2019/06/22 06:00
CRDT- 2019/03/08 06:00
PHST- 2018/08/06 00:00 [received]
PHST- 2019/01/07 00:00 [revised]
PHST- 2019/01/08 00:00 [accepted]
PHST- 2019/03/08 06:00 [entrez]
PHST- 2019/03/08 06:00 [pubmed]
PHST- 2019/06/22 06:00 [medline]
AID - S0753-3322(18)35443-X [pii]
AID - 10.1016/j.biopha.2019.01.028 [doi]
PST - ppublish
SO  - Biomed Pharmacother. 2019 Mar;111:1353-1358. doi: 10.1016/j.biopha.2019.01.028. 
      Epub 2019 Jan 17.