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AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics

Oncogene volume 39, pages 2707–2723 (2020)Cite this article

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Abstract

Mitochondrial fusion and fission dynamics fine-tune cellular calcium homeostasis, ATP production capacity and ROS production and play important roles in cell proliferation and migration. Dysregulated mitochondrial dynamics is closely related to tumor development, but the mechanism of mitochondrial dynamics dysregulation and its role in the development of lung cancer remains unclear. Here, we demonstrate that the DNA sensor protein absent in melanoma 2 (AIM2) is highly expressed in non-small cell lung cancer (NSCLC) cells and that high AIM2 expression is associated with poor prognosis in patients with NSCLC. High expression of AIM2 contributes to tumor cell growth and proliferation independent of inflammasome activation in vitro and in vivo. Further studies have shown that AIM2 colocalizes with mitochondria in NSCLC cells and that AIM2 knockdown leads to enhanced mitochondrial fusion and decreased cell proliferation. Mechanistic studies have shown that AIM2 downregulation promotes MFN2 upregulation, thereby enhancing mitochondrial fusion. Moreover, we found that mitochondrial fusion driven by AIM2 knockdown leads to a decrease of cellular reactive oxygen species (ROS) production, which further causes inactivation of the MAPK/ERK signaling pathway. Together, we discovered a novel function of AIM2 in promoting NSCLC development by regulating mitochondrial dynamics and revealed its underlying mechanism. Our work provides new intervention targets for the treatment of NSCLC.

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Fig. 1: AIM2 is highly expressed in NSCLC cells, and its expression correlates with poor survival of patients.
Fig. 2: AIM2 promotes NSCLC cell growth and proliferation in vitro and tumorigenesis in vivo that is independent of inflammasome activation.
Fig. 3: AIM2 colocalizes in mitochondria in NSCLC cells.
Fig. 4: AIM2 regulates mitochondrial dynamics by MFN2 in NSCLC cells.
Fig. 5: Mitochondria fusion enhancement suppressed cell proliferation in NSCLC cells.
Fig. 6: Mitochondrial dynamics regulated cell proliferation by regulating MAPK/ERK signaling pathway.
Fig. 7: Mitochondria dynamics regulated ERK activation by ROS production.

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Acknowledgements

We are thankful for financial support of National Natural Science Foundation of China (81872250), the Natural Science Foundation of Shaanxi Province, China (2016JM8102), the key industrial chain projects of Shaanxi Province (2019TD-033), the program of Innovative Research Team for the Central Universities (GK201701005), and the Student Innovation Training Program (201810718056, 201910718048), Shaanxi Normal University. The authors like to thank Dr Ling Guo and Yaohui Ren for assistance with TEM.

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  1. These authors contributed equally: Miao Qi, Dan Dai, Jin Liu

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  1. National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, Xi’an, 710119, Shaanxi, China

    Miao Qi, Dan Dai, Jin Liu, Zhongqi Li, Panpan Liang, Yue Wang, Lu Cheng, Yihong Zhan, Zhifeng An, Yaoyao Song, Yana Yang, Xiaohui Yan, Hui Xiao & Huanjie Shao

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Qi, M., Dai, D., Liu, J. et al. AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics. Oncogene 39, 2707–2723 (2020). https://doi.org/10.1038/s41388-020-1176-9

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