Erk1/2 Signaling Plays An Important Role In The Topoisomerase Ii Inhibitor Induced G2/M Checkpoint Response

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Topoisomerase II inhibitors, such as Etoposide and Doxorubicin, are commonly used radiomimetic chemotherapeutic agents. These drugs can induce G2/M cell cycle arrest which allows time for the cell to repair the damaged DNA. The induction of G2/M arrest involves the activation of ATM and ATR kinases which activate Chk1 and Chk2 kinases respectively. Chk1 and Chk2 inhibit Cdc25 phosphatases from activating Cdc2 kinase that is required for the G2/M transition of the cell cycle. While previous studies have shown that ERK1/2 signaling is required for the induction of G2/M arrest by topoisomerase II inhibitors in MCF-7 breast cancer cells, the role it plays has not been clearly defined. Using the MEK1/2 specific inhibitor U0126 to inhibit ERK1/2 signaling, the data presented in this study shows that ERK1/2 signaling is required for ATR and Chk1 activation and G2/M arrest following exposure to topoisomerase II inhibitors in MCF-7 cells. Consistently knocking down ERK1/2 by siRNA or ATR by shRNA mimics the effect of U0126 resulting in the attenuation of G2/M arrest induction by Doxorubicin. In contrast, inhibiting ERK1/2 signaling with U0126 had no effect on the activation of ATM and Chk2 activity following exposure to topoisomerase II inhibitors. In addition knocking down ATM had no effect on the induction of G2/M arrest by doxorubicin. This data suggests that, though topoisomerase II inhibitors induce both ATR and ATM activity, only ATR mediated signaling which is regulated by ERK1/2 is involved in the induction of G2/M arrest. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2485.