Inhibitors of the PI3-kinase/Akt pathway induce mitotic catastrophe in non-small cell lung cancer cells

✍ Scribed by Therese H Hemström; Margareta Sandström; Boris Zhivotovsky

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 696 KB
• Volume: 119
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21927

✦ Synopsis

Abstract

Non‐small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemström et al., Exp Cell Res 2005;305:200–13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3‐kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3‐kinase inhibitors LY‐294002 and wortmannin, the Akt activator Ro 31‐8220, the MEK inhibitor PD 98059 and PKC 412. PI3‐kinase inhibitors induced apoptosis‐like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA‐damaging drug VP‐16, while Ro 31‐8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3‐kinase inhibition and VP‐16. Morphological data indicated that LY‐294002 and PKC 412 induced cell death at anaphase and metaphase, respectively, suggesting death by mitotic catastrophe. Analyzes of cells blocked in G2/M‐phase by nocodazol revealed that LY‐294002 increased, while PKC 412 decreased histone H3 phosphorylation, suggesting that LY‐294002 allowed, while PKC 412 inhibited cells to leave M‐phase. Flow cytometric analysis of cell cycle distribution demonstrated that LY‐294002 allowed cells to leave G2/M phase, while PKC 412 inhibited cytokinesis, resulting in formation of multinucleated cells. These results indicate that sensitization of NSCLC cells by PI3‐kinase inhibition involves interplay between cell cycle regulation, mitotic catastrophe and apoptosis. © 2006 Wiley‐Liss, Inc.