PMID- 25446102
OWN - NLM
STAT- MEDLINE
DCOM- 20150310
LR  - 20161125
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 456
IP  - 1
DP  - 2015 Jan 2
TI  - Inhibition of MEK/ERK activation attenuates autophagy and potentiates 
      pemetrexed-induced activity against HepG2 hepatocellular carcinoma cells.
PG  - 86-91
LID - S0006-291X(14)02050-6 [pii]
LID - 10.1016/j.bbrc.2014.11.038 [doi]
AB  - Identification of efficient chemo-therapeutic/chemo-preventive agents for 
      treatment of hepatocellular carcinoma (HCC) is important. In this study, we 
      examined the activity of pemetrexed, an anti-folate chemotherapy drug, against 
      HepG2 human HCC cells. Pemetrexed treatment in vitro exerted weak but significant 
      cytotoxic activity against HepG2 cells. When analyzing the possible 
      pemetrexed-resistance factors, we indentified that pemetrexed treatment in HepG2 
      cells induced cyto-protective autophagy activation, evidenced by GFP-light chain 
      3B (LC3B) puncta formation, p62 downregulation and Beclin-1/LC3B-II upregulation. 
      Correspondingly, autophagy inhibitors, including bafliomycin A1, 3-methyladenine 
      and chloroquine, enhanced pemetrexed-induced cytotoxicity against HepG2 cells. 
      Further, RNAi-mediated knockdown of Beclin-1 in HepG2 cells also increased 
      pemetrexed sensitivity. Pemetrexed activated MEK (mitogen-activated protein 
      kinase/ERK kinase)/ERK (extracellular-signal-regulated kinase) signaling in HepG2 
      cells, which was required for autophagy induction. Pharmacological inhibition of 
      MEK/ERK activation attenuated pemetrexed-induced autophagy, enhanced HepG2 cell 
      death and apoptosis. In summary, pemetrexed activates MEK/ERK-dependent 
      cyto-protective autophagy, and inhibition of this pathway potentiates 
      pemetrexed's activity in HepG2 cells.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Tong, Yongxi
AU  - Tong Y
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China. Electronic address: tongyongxi75@2980.com.
FAU - Huang, Haijun
AU  - Huang H
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China.
FAU - Pan, Hongying
AU  - Pan H
AD  - Department of Infectious Disease, Zhejiang Province People's Hospital, Hangzhou, 
      China. Electronic address: panhongyinghz@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141121
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BECN1 protein, human)
RN  - 0 (Beclin-1)
RN  - 0 (Glutamates)
RN  - 0 (Membrane Proteins)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
SB  - IM
MH  - Antimetabolites, Antineoplastic/*pharmacology
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Autophagy
MH  - Beclin-1
MH  - Carcinoma, Hepatocellular/*metabolism/pathology
MH  - Cell Death
MH  - Cell Survival
MH  - Drug Screening Assays, Antitumor
MH  - Enzyme Activation/drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Glutamates/*pharmacology
MH  - Green Fluorescent Proteins/metabolism
MH  - Guanine/*analogs & derivatives/pharmacology
MH  - Hep G2 Cells
MH  - Humans
MH  - Liver Neoplasms/*metabolism/pathology
MH  - MAP Kinase Kinase Kinases/*metabolism
MH  - Membrane Proteins/metabolism
MH  - Pemetrexed
MH  - RNA Interference
MH  - Signal Transduction
OTO - NOTNLM
OT  - Autophagy
OT  - Chemo-sensitization
OT  - Hepatocellular carcinoma (HCC)
OT  - MEK/ERK signaling
OT  - Pemetrexed
EDAT- 2014/12/03 06:00
MHDA- 2015/03/11 06:00
CRDT- 2014/12/03 06:00
PHST- 2014/11/13 00:00 [received]
PHST- 2014/11/15 00:00 [accepted]
PHST- 2014/12/03 06:00 [entrez]
PHST- 2014/12/03 06:00 [pubmed]
PHST- 2015/03/11 06:00 [medline]
AID - S0006-291X(14)02050-6 [pii]
AID - 10.1016/j.bbrc.2014.11.038 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2015 Jan 2;456(1):86-91. doi: 
      10.1016/j.bbrc.2014.11.038. Epub 2014 Nov 21.