Abstract 1975: AICAR induces cell death in LKB1-deficient NSCLC.

Abstract

Abstract AICAR is a well known AMPK activator, and AICAR-induced AMPK activation has been shown to inhibit cell proliferation or induce apoptosis through various mechanisms, such as the inactivation of metabolic enzyme involved ATP consumption, the inhibition of the of fatty acid synthesisPI3K/AKT pathway, the activation of cell cycle regulators, or the activation of the JNK pathway. LKB1 is an upstream AMPK kinase, and energetic stress-induced AMPK activation usually requires LKB1. Interestingly, AICAR has also been shown to induce caspase-3 cleavage in LKB1- null MEF and ovarian cancer cells, indicating AICAR can induce cell killing through an AMPK- independent mechanism. Because LKB1 is most frequently inactivated in non-small cell lung cancer, we evaluated the effect of AICAR in lung cancer cell lines. AICAR preferentially induced caspase-3 cleavage in LKB1- mutant NSCLC cell lines H157, A549, H460 and H1944, but not in LKB1- wild type cell lines H1299, H358, H1650 and H1792. Transient depletion of LKB1 by RNAi in H1299 and H1792 cells promoted AICAR-induced caaspase-3 cleavage in the absence of AMPK activation, supporting the notion that AICAR induces cell killing in LKB1-depleted cells through an AMPK- independent mechanism. In LKB1-null H460 cells, AICAR treatment led to a significant increase in S phase cell populations, and G1 cell cycle arrest by serum starvation is was sufficient to prevent AICAR-induced cell death. These data indicated that AICAR-induced cell killing in LKB1- deficient cells is cell cycle dependent. In summary, the ability of AICAR to preferentially induce cell death in LKB1- deficient NSCLC suggestsed that LKB1 deficiency may be a therapeutic target for the treatment of NSCLC. Citation Format: Fakeng Liu, Wei Zhou, Xiuju Liu, Shi-yong Sun, Fadlo Khuri, Yu-long He, Diansheng Zhong. AICAR induces cell death in LKB1-deficient NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1975. doi:10.1158/1538-7445.AM2013-1975