PMID- 23794518
OWN - NLM
STAT- MEDLINE
DCOM- 20140506
LR  - 20181202
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Linking)
VI  - 114
IP  - 12
DP  - 2013 Dec
TI  - Autophagy stimulates apoptosis in HER2-overexpressing breast cancers treated by 
      lapatinib.
PG  - 2643-53
LID - 10.1002/jcb.24611 [doi]
AB  - HER2-overexpressing breast cancers often show hyperactivation of the 
      HER2/AKT/mTOR signaling pathway. Lapatinib is an oral dual tyrosine kinase 
      inhibitor (TKI) that targets both EGFR and HER2 to inhibit the proliferation of 
      breast cancer cells. However, it is obscure whether and how lapatinib could 
      induce autophagy in breast cancer cells, an important cell response with drug 
      treatment. In this study, we investigated the apoptosis and the autophagy in the 
      HER2-overexpressing breast cancer cells BT474 and AU565 treated with lapatinib, 
      and further examined their relationship. Lapatinib inhibited the proliferation 
      and the rate of DNA synthesis in HER2-positive cells, as observed by MTT, colony 
      formation and EDU assays. Lapatinib not only induced apoptosis accompanied by an 
      increased expression of cleaved Caspase-3 and cleaved PARP, but it also induced 
      autophagy in vitro, as confirmed by electron microscopy (EM), acridine orange 
      (AO) staining and LC3-II expression. Meanwhile, lapatinib inhibited the 
      phosphorylation of HER2, AKT, mTOR, and p70S6K, whereas that of AMPK was 
      activated. When the cells were pre-incubated with 3-Methyladenine (3-MA), the 
      specific autophagy inhibitor, the growth inhibitory ratio and apoptosis rate were 
      frustrated, whereas colony formation and DNA synthesis ability were encouraged. 
      In addition, 3-MA application could up-regulate Caspase-3 and PARP expression, 
      compared with the treatment with lapatinib alone. The addition of 3-MA could 
      attenuate the inhibitory role on HER2/AKT/mTOR pathway and the active role on 
      AMPK that was raised by lapatinib. Therefore, lapatinib simultaneously induced 
      both apoptosis and autophagy in the BT474 and AU565 cells, and in these settings, 
      autophagy facilitates apoptosis.
CI  - (c) 2013 Wiley Periodicals, Inc.
FAU - Zhu, Xingmei
AU  - Zhu X
AD  - Department of Pharmaceutical Chemistry, The Fourth Military Medical University, 
      Xi'an, Shaanxi, 710032, China.
FAU - Wu, Lin
AU  - Wu L
FAU - Qiao, Hongyu
AU  - Qiao H
FAU - Han, Tenglong
AU  - Han T
FAU - Chen, Suning
AU  - Chen S
FAU - Liu, Xueying
AU  - Liu X
FAU - Jiang, Ru
AU  - Jiang R
FAU - Wei, Yifang
AU  - Wei Y
FAU - Feng, Dayun
AU  - Feng D
FAU - Zhang, Yuan
AU  - Zhang Y
FAU - Ma, Yongzheng
AU  - Ma Y
FAU - Zhang, Shengyong
AU  - Zhang S
FAU - Zhang, Jian
AU  - Zhang J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0VUA21238F (Lapatinib)
RN  - 5142-23-4 (3-methyladenine)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/administration & dosage/analogs & derivatives
MH  - Apoptosis/*drug effects
MH  - Autophagy/*drug effects
MH  - Breast Neoplasms/*drug therapy/genetics/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Lapatinib
MH  - Phosphorylation
MH  - Protein Kinase Inhibitors
MH  - Quinazolines/*administration & dosage
MH  - Receptor, ErbB-2/antagonists & inhibitors/*genetics
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - AMPK
OT  - APOPTOSIS
OT  - AUTOPHAGY
OT  - BREAST CANCER
OT  - LAPATINIB
OT  - mTOR
EDAT- 2013/06/25 06:00
MHDA- 2014/05/07 06:00
CRDT- 2013/06/25 06:00
PHST- 2013/03/15 00:00 [received]
PHST- 2013/06/11 00:00 [accepted]
PHST- 2013/06/25 06:00 [entrez]
PHST- 2013/06/25 06:00 [pubmed]
PHST- 2014/05/07 06:00 [medline]
AID - 10.1002/jcb.24611 [doi]
PST - ppublish
SO  - J Cell Biochem. 2013 Dec;114(12):2643-53. doi: 10.1002/jcb.24611.