Abstract
Lung cancer is the second most common cause of cancer-related death in the world. Most cases of lung cancer are not curable, especially non-small cell lung cancer (NSCLC). Thus, novel treatment targets for this malignant disease are urgently needed. Here, we demonstrate the feasibility of Rac1 in treating p53-null human NSCLC H1299 as a novel drug target. Deacetylmycoepoxydiene (DA-MED), a cytotoxic natural polyketide, functions as a Rac1 agonist in p53-null NSCLC H1299 cells. DA-MED treatment drives Rac1 activation and promotes robust production of reactive oxygen species, activating mitochondrial permeability transition and the intrinsic apoptotic pathway. Knockdown of Rac1 decreases ROS production in DA-MED-treated cells, resulting in a concomitant decrease in DA-MED-induced apoptosis. DA-MED-activated Rac1 induces autophagy by inhibiting mammalian target of rapamycin, leading to anti-apoptotic and anti-metastatic effects. Therefore, this study provides novel insight into the complex cytotoxic and pro-survival mechanisms associated with a potent Rac1 agonist and suggests that further development of more potent Rac1 agonists could be an effective strategy for future non-small cell lung cancer treatments.
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Funding
This work was supported by the National Natural Science Foundation of China (91,313,303, 81,373,304, U1405223), Program for Changjiang Scholars and Innovative Research Team in University (IRT_17R68), the National Natural Science Funds for Distinguished Young Scholars to Y.S. (30325044), and Postdoctoral innovation fund of Shandong Province (201502026).
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Xie, W., Zhang, W., Sun, M. et al. Deacetylmycoepoxydiene is an agonist of Rac1, and simultaneously induces autophagy and apoptosis. Appl Microbiol Biotechnol 102, 5965–5975 (2018). https://doi.org/10.1007/s00253-018-9058-6
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DOI: https://doi.org/10.1007/s00253-018-9058-6