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A mitophagy-mediated autophagy pathway that triggers apoptotic cell death in non-small cell lung cancer (NSCLC) for anticancer chemotherapy by Norcantharidin
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  • jinyan zhu,
  • Baoxia Li,
  • Jinhua He,
  • Qiuyun Luo,
  • Liting Dai,
  • Xiaofeng Zhu,
  • Dajun Yang,
  • Jianwei Jiang
jinyan zhu
Jinan University
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Baoxia Li
Sun Yat-sen University Cancer Center
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Jinhua He
Guangzhou Panyu Central Hospital
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Qiuyun Luo
Sun Yat-sen University State Key Laboratory of Oncology in South China
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Liting Dai
Jinan University
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Xiaofeng Zhu
Sun Yat-sen University Cancer Center
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Dajun Yang
Sun Yat-sen University State Key Laboratory of Oncology in South China
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Jianwei Jiang
Jinan University
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Abstract

Norcantharidin (NCTD) is a traditional Chinese medicine (TCM) that has been used for over 2000 years to treat many diseases. It can inhibit proliferation and induce apoptosis in multiple types of cancer cells. However, the anticancer activities of NCTD in non-small cell lung cancer (NSCLC) cells, and its underlying mechanisms, have not been investigated. In this study, NCTD suppressed the growth and proliferation of A549 non-small cell lung cancer cells in a dose-dependent manner, apparently by reducing the mitochondrial membrane potential and inducing G2/M phase arrest. NCTD induced apoptosis by increasing the ratio of Bax/Bcl-2 and Bax/Mcl-1 and activating caspase-3/9-dependent mitochondrial pathways. Treatment with NCTD induced significant mitophagy and autophagy, as the demonstrated by accumulation of punctate LC3 in the cytoplasm and the characteristic clustering of the mitochondria around the nucleus, increasing the conversion of LC3-I to LC3-II and reducing the protein expression of p62. In addition, we also observed an increase in p-AMPK, p-JNK and p-c-jun and decrease in p-AKT and mTOR. In conclusion, our results demonstrate that NCTD can reduce the mitochondrial membrane potential and subsequently increase cellular autophagy and apoptosis; the AMPK/mTOR/ULK1, JNK and Akt/mTOR signaling pathways were involved in these processes. Thus, the traditional Chinese medicine NCTD could be a novel therapeutic for treating NSCLC cells.