title: Non-small cell lung cancer cell survival crucially depends on functional insulin receptors.
abstract: 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.
authors.affiliation: 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.
authors.forename: Carolin Maria
authors.initials: CM
authors.lastname: Frisch
authors.affiliation: 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.
authors.forename: Katrin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: 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.
authors.forename: Pia
authors.initials: P
authors.lastname: Zilleßen
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: 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.
authors.forename: Kurt
authors.initials: K
authors.lastname: Racké
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D007328:Insulin; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: IGF receptor; apoptosis; carcinoma; insulin; insulin receptor