title: Alterations of phosphoproteins in NCI-H526 small cell lung cancer cells involved in cytotoxicity of cisplatin and titanocene Y.
abstract: First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cis-diamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds.
authors.affiliation: Ludwig Boltzmann Society, Cluster of Translational Oncology, Vienna, Austria. ulrike.olszewski@toc.lbg.ac.at
authors.forename: Ulrike
authors.initials: U
authors.lastname: Olszewski
authors.forename: Anthony
authors.initials: A
authors.lastname: Deally
authors.forename: Matthias
authors.initials: M
authors.lastname: Tacke
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hamilton
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; C518838:Titanocene Y; D016159:Tumor Suppressor Protein p53; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin