PMID- 21159653
OWN - NLM
STAT- MEDLINE
DCOM- 20110120
LR  - 20191210
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 70
IP  - 24
DP  - 2010 Dec 15
TI  - Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung 
      cancers positive for EGFR mutations.
PG  - 10402-10
LID - 10.1158/0008-5472.CAN-10-2438 [doi]
AB  - The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase 
      inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) 
      cells that are positive for activating mutations of the EGFR remains unclear. In 
      this study, we report the effects of the EGFR-TKI gefitinib on expression of the 
      antiapoptotic protein survivin that have functional consequences in EGFR 
      mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib 
      downregulated survivin expression, likely through inhibition of the PI3K-AKT 
      signaling pathway, in NSCLC cells positive for EGFR mutation. Stable 
      overexpression of survivin attenuated gefitinib-induced apoptosis and also 
      inhibited the antitumor effect of gefitinib in human tumor xenografts. 
      Furthermore, the combination of survivin overexpression with inhibition of the 
      gefitinib-induced upregulation of the proapoptotic protein BIM attenuated 
      gefitinib-induced apoptosis to a greater extent than either approach alone. Our 
      results indicate that downregulation of survivin plays a pivotal role in 
      gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, 
      they suggest that simultaneous interruption of the PI3K-AKT-survivin and 
      MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic 
      death in these cells.
CI  - (c)2010 AACR.
FAU - Okamoto, Kunio
AU  - Okamoto K
AD  - Department of Medical Oncology, Kinki University School of Medicine, 377-2 
      Ohno-higashi, Osaka-Sayama, Osaka, Japan.
FAU - Okamoto, Isamu
AU  - Okamoto I
FAU - Okamoto, Wataru
AU  - Okamoto W
FAU - Tanaka, Kaoru
AU  - Tanaka K
FAU - Takezawa, Ken
AU  - Takezawa K
FAU - Kuwata, Kiyoko
AU  - Kuwata K
FAU - Yamaguchi, Haruka
AU  - Yamaguchi H
FAU - Nishio, Kazuto
AU  - Nishio K
FAU - Nakagawa, Kazuhiko
AU  - Nakagawa K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BCL2L11 protein, human)
RN  - 0 (BIRC5 protein, human)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Survivin)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Apoptosis/*drug effects/physiology
MH  - Apoptosis Regulatory Proteins/biosynthesis/genetics
MH  - Bcl-2-Like Protein 11
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*enzymology/genetics/pathology
MH  - Cell Line, Tumor
MH  - Down-Regulation/drug effects
MH  - ErbB Receptors/*antagonists & inhibitors/genetics/metabolism
MH  - Gefitinib
MH  - Gene Knockdown Techniques
MH  - *Genes, erbB-1
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - Lung Neoplasms/drug therapy/*enzymology/genetics/pathology
MH  - Membrane Proteins/biosynthesis/genetics
MH  - Microtubule-Associated Proteins/*biosynthesis/genetics
MH  - *Mutation
MH  - Oncogene Protein v-akt/antagonists & inhibitors/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins/biosynthesis/genetics
MH  - Quinazolines/*pharmacology
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Survivin
EDAT- 2010/12/17 06:00
MHDA- 2011/01/21 06:00
CRDT- 2010/12/17 06:00
PHST- 2010/12/17 06:00 [entrez]
PHST- 2010/12/17 06:00 [pubmed]
PHST- 2011/01/21 06:00 [medline]
AID - 70/24/10402 [pii]
AID - 10.1158/0008-5472.CAN-10-2438 [doi]
PST - ppublish
SO  - Cancer Res. 2010 Dec 15;70(24):10402-10. doi: 10.1158/0008-5472.CAN-10-2438.