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LKB1 Loss Sensitizes Lung Tumor Spheres to Mitomet-Induced Ferroptosis, and These Effects are Enhanced by mTOR Inhibition
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DOI：10.1002/mc.70129.png)
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Abstract
En 中文
Owing to their robust antioxidant defense mechanisms, cancer stem-like cells (CSCs) maintain a low level of oxidative stress, which is crucial for preserving stemness and pluripotency. Therefore, agents that either directly generate reactive oxygen species (ROS) or inhibit the antioxidant defense systems can selectively induce oxidative cell death in CSCs. Loss of the tumor suppressor gene LKB1 makes CSCs more vulnerable to oxidative damage, as these cells cannot sense energy stress. In the present study, LKB1 wild-type (WT) and LKB1 mutant isogenic non-small cell lung cancer (NSCLC) cells were grown in sphere culture media, which enriches the CSC population, and treated with mitomet, an analog of the antidiabetic drug metformin. Subsequently, effects on self-renewal of spheres, mitochondrial membrane potential (MMP), ATP synthesis, expression of self-renewal-, cell proliferation/survival-, redox metabolism-, and lipid synthesis-related proteins, mitochondrial ROS (mROS), lipid peroxidation, and cell proliferation/survival were determined. Mitomet differentially increased mROS in LKB1 mutant tumor spheres, thereby suppressing levels of MMP, ATP synthesis, GPX4, and phospho-ACC, which then culminated in increased lipid peroxidation and cell death. Mitomet-induced lipid peroxidation and cell death were reversed by liproxstatin, a potent inhibitor of ferroptosis, indicating that mitomet-induced cell death was mediated via ferroptosis. Interestingly, Torin-1, an mTOR inhibitor, significantly potentiated lipid peroxidation and ferroptosis induced by mitomet. Our findings establish the potential of mitomet, especially when combined with mTOR inhibitors, for the prevention and treatment of LKB1 mutant lung cancer by targeting CSCs.
Keywords:
cancer stem cells
ferroptosis
LKB1 loss
mitochondria
Mitomet
non-small cell lung cancer
spheres
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