Abstract
BackgroundCellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. In recent studies, we demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation.Methodology/Principal FindingsIn this study, we evaluated the effects of lovastatin on the activity of the LKB1/AMPK pathway that is activated upon cellular energy shortage and can interact with the above pathways. In the squamous cell carcinoma (SCC) cell lines SCC9 and SCC25, lovastatin treatment (1–25 µM, 24 hrs) induced LKB1 and AMPK activation similar to metformin (1–10 mM, 24 hrs), a known inducer of this pathway. Lovastatin treatment impaired mitochondrial function and also decreased cellular ADP/ATP ratios, common triggers of LKB1/AMPK activation. The cytotoxic effects of lovastatin were attenuated in LKB1 null MEFs indicating a role for this pathway in regulating lovastatin-induced cytotoxicity. Of clinical relevance, lovastatin induces synergistic cytotoxicity in combination with the EGFR inhibitor gefitinib. In LKB1 deficient (A549, HeLa) and expressing (SCC9, SCC25) cell lines, metformin enhanced gefitinib cytotoxicity only in LKB1 expressing cell lines while both groups showed synergistic cytotoxic effects with lovastatin treatments. Furthermore, the combination of lovastatin with gefitinib induced a potent apoptotic response without significant induction of autophagy that is often induced during metabolic stress inhibiting cell death.Conclusion/SignificanceThus, targeting multiple metabolic stress pathways including the LKB1/AMPK pathway enhances lovastatin’s ability to synergize with gefitinib in SCC cells.
Highlights
A fundamental requirement of all cells is the ability to adapt to changes in their environment that includes the availability of nutrients required to maintain homeostasis or to trigger proliferation only when they are in sufficient supply [1,2]
We have previously shown that lovastatin can induce tumour specific apoptosis especially in squamous cell carcinomas (SCC) [16] and that 23% of SCC patients treated with lovastatin as a single agent showed disease stabilization in our Phase I clinical trial [17]
Another metabolic stress pathway, induced by Liver Kinase B1 (LKB1)/ AMPK activation, has common downstream targets to these pathways [11] (Figure 1A) and the goal of this study was to evaluate the potential of lovastatin to activate LKB1/AMPK and determine their role in regulating lovastatin-induced apoptosis of SCC cells
Summary
A fundamental requirement of all cells is the ability to adapt to changes in their environment that includes the availability of nutrients required to maintain homeostasis or to trigger proliferation only when they are in sufficient supply [1,2]. Under conditions of metabolic stress where nutrients are limited, a number of cellular stress pathways can be activated that attempt to alleviate this stress or if the stress cannot be overcome to induce apoptosis [3,4,5]. Hypoxia, amino acid starvation, growth factor withdrawal and conditions or agents that affect ATP synthesis are all common triggers of metabolic stress [1,2]. Cellular stress responses trigger signaling cascades that inhibit proliferation and protein translation to help alleviate the stress or if the stress cannot be overcome induce apoptosis. We demonstrated the ability of lovastatin, an inhibitor of mevalonate synthesis, to induce the Integrated Stress Response as well as inhibiting epidermal growth factor receptor (EGFR) activation
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