title: Metformin Triggers Autophagy to Attenuate Drug-Induced Apoptosis in NSCLC Cells, with Minor Effects on Tumors of Diabetic Patients.
abstract: The biologic plausibility of an association between type 2 diabetes mellitus (T2D) and lung cancer has received increasing attention, but the results of investigations remain largely inconclusive. In the present study we investigated the influence of the anti-diabetic drug metformin on the cytotoxic effects of EGFR targeted therapy and chemotherapy in 7 non-small cell lung cancer (NSCLC) cell lines and a cohort of lung cancer patients with/without T2D. In vitro cell viability assays indicated that metformin didn't potentiate the growth inhibitory effects of erlotinib at different doses in cell lines that are of distinct genetic background. EGFR downstream signaling evaluation further demonstrated that metformin, at its IC50value, modified apoptosis caused in erlotinib or chemotherapeutic agent-treated cells via AKT activation and the inhibition of caspase 3 and PARP cleavages. These regulations were driven independently from EGFR, LKB1, KRAS, PTEN and p53 status. Metformin triggered autophagy (LC3B expression) was identified to interplay with apoptosis to attenuate the drug effect and postpone cancer cell death. In the retrospective study of 8 NSCLC patients, the administration of metformin did not induce statistically significant changes as assessed by immunohistochemical staining of pERK, pAKT and cleaved PARP. Consequently, the application of metformin for T2D NSCLC patients receiving chemo or EGFR targeted therapy should be considered with caution.
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, Germany.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gaertner
authors.affiliation: Asklepios Institute of Pathology, Munich-Gauting, Robert-Koch Alee, 2, D-82131, Germany.
authors.forename: Alicia
authors.initials: A
authors.lastname: Morresi-Hauf
authors.affiliation: Asklepios Lung Clinic, Munich-Gauting, Robert-Koch Alee, 2; D-82131, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Genzel
authors.affiliation: Asklepios Lung Clinic, Munich-Gauting, Robert-Koch Alee, 2; D-82131, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duell
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18a, Martinsried, D-82152, Germany. Electronic address: knyazev@biochem.mpg.de.
authors.forename: Pjotr G
authors.initials: PG
authors.lastname: Knyazev
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D008687:Metformin; D000069347:Erlotinib Hydrochloride; D000071137:Poly (ADP-Ribose) Polymerase-1; C512478:EGFR protein, human; D066246:ErbB Receptors