PMID- 26113601
OWN - NLM
STAT- MEDLINE
DCOM- 20160411
LR  - 20150806
IS  - 1479-6821 (Electronic)
IS  - 1351-0088 (Linking)
VI  - 22
IP  - 4
DP  - 2015 Aug
TI  - Non-small cell lung cancer cell survival crucially depends on functional insulin 
      receptors.
PG  - 609-21
LID - 10.1530/ERC-14-0581 [doi]
AB  - Insulin plays an important role as a growth factor and its contribution to tumor 
      proliferation is intensely discussed. It acts via the cognate insulin receptor 
      (IR) but can also activate the IGF1 receptor (IGF1R). Apart from increasing 
      proliferation, insulin might have additional effects in lung cancer. Therefore, 
      we investigated insulin action and effects of IR knockdown (KD) in three 
      (NCI-H292, NCI-H226 and NCI-H460) independent non-small cell lung cancer (NSCLC) 
      cell lines. All lung cancer lines studied were found to express IR, albeit with 
      marked differences in the ratio of the two variants IR-A and IR-B. Insulin 
      activated the classical signaling pathway with IR autophosphorylation and Akt 
      phosphorylation. Moreover, activation of MAPK was observed in H292 cells, 
      accompanied by enhanced proliferation. Lentiviral shRNA IR KD caused strong 
      decrease in survival of all three lines, indicating that the effects of insulin 
      in lung cancer go beyond enhancing proliferation. Unspecific effects were ruled 
      out by employing further shRNAs and different insulin-responsive cells (human 
      pre-adipocytes) for comparison. Caspase assays demonstrated that IR KD strongly 
      induced apoptosis in these lung cancer cells, providing the physiological basis 
      of the rapid cell loss. In search for the underlying mechanism, we analyzed 
      alterations in the gene expression profile in response to IR KD. A strong 
      induction of certain cytokines (e.g. IL20 and tumour necrosis factor) became 
      obvious and it turned out that these cytokines trigger apoptosis in the NSCLC 
      cells tested. This indicates a novel role of IR in tumor cell survival via 
      suppression of pro-apoptotic cytokines.
CI  - (c) 2015 Society for Endocrinology.
FAU - Frisch, Carolin Maria
AU  - Frisch CM
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
FAU - Zimmermann, Katrin
AU  - Zimmermann K
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
FAU - Zillessen, Pia
AU  - Zillessen P
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
FAU - Pfeifer, Alexander
AU  - Pfeifer A
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
FAU - Racke, Kurt
AU  - Racke K
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany.
FAU - Mayer, Peter
AU  - Mayer P
AD  - Institute of Pharmacology and ToxicologyUniversity of Bonn, Sigmund-Freud-Strasse 
      25, 53127 Bonn, GermanyFederal Institute for Drugs and Medical Devices 
      (BfArM)Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany Peter.Mayer@bfarm.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150625
PL  - England
TA  - Endocr Relat Cancer
JT  - Endocrine-related cancer
JID - 9436481
RN  - 0 (Antigens, CD)
RN  - 0 (Cytokines)
RN  - 0 (Insulin)
RN  - EC 2.7.10.1 (INSR protein, human)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Antigens, CD/genetics/*metabolism
MH  - Apoptosis
MH  - Carcinoma, Non-Small-Cell Lung/*metabolism
MH  - Cell Line, Tumor
MH  - Cytokines/metabolism
MH  - Gene Expression Profiling
MH  - Humans
MH  - Insulin/pharmacology
MH  - Lung Neoplasms/*metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Receptor, IGF Type 1/genetics/metabolism
MH  - Receptor, Insulin/genetics/*metabolism
OTO - NOTNLM
OT  - IGF receptor
OT  - apoptosis
OT  - carcinoma
OT  - insulin
OT  - insulin receptor
EDAT- 2015/06/27 06:00
MHDA- 2016/04/12 06:00
CRDT- 2015/06/27 06:00
PHST- 2015/05/28 00:00 [accepted]
PHST- 2015/06/27 06:00 [entrez]
PHST- 2015/06/27 06:00 [pubmed]
PHST- 2016/04/12 06:00 [medline]
AID - ERC-14-0581 [pii]
AID - 10.1530/ERC-14-0581 [doi]
PST - ppublish
SO  - Endocr Relat Cancer. 2015 Aug;22(4):609-21. doi: 10.1530/ERC-14-0581. Epub 2015 
      Jun 25.