Alterations of Phosphoproteins in NCI-H526 Small Cell Lung Cancer Cells Involved in Cytotoxicity of Cisplatin and Titanocene Y

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 p38 alpha mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha 1 (AMPK alpha 1) 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-beta-D-ribofuranoside. This is in good agreement with previous reports, where AMPK alpha 1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPK alpha 1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds. Neoplasia (2012) 14, 813-822