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Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation

Oncogenevolume 38pages18321844 (2019) | Download Citation


Pancreatic cancer remains one of the deadliest human cancers despite current advances in conventional therapeutics including surgery and adjuvant therapies. Here, we showed that LZ1, a peptide derived from a snake venom cathelicidin, significantly inhibited growth of pancreatic cancer cells by inducing autophagy-dependent cell death both in vitro and in vivo. The LZ1-induced cell death was blocked by pharmacological or genetic inhibition of autophagy. In orthotopic model of pancreatic cancer, systemic administration of LZ1 (1–4 mg/kg) exhibited remarkable antitumor efficacy, significantly prolonged mice survival, and showed negligible adverse effects by comparison with gemcitabine (20 mg/kg). Mechanistic studies revealed that LZ1 acts through binding to nucleolin, whose expression on cell surface is frequently increased in pancreatic cancer cells. LZ1 binding triggers degradation of surface-expressed nucleolin. This leads to activation of 5′-AMP kinase which results in suppression of mTORC1 activity and induction of autophagic flux. These data suggest that LZ1, targeting nucleolin–AMPK–autophagy axis, is a promising lead for the development of therapeutic agents against pancreatic cancer.

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These authors contributed equally: Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang


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This work was supported by National Natural Science Foundation of China (21761142002 and 81770464), Ministry of Science and Technology (2018ZX09301043-003), Chinese Academy of Science (QYZDJ-SSWSMC012, SAJC201606, the West Light Foundation and Youth Innovation Promotion Association (2017432)) and Yunnan Provincial Science and Technology Department (2017FB038, 2015BC005).

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Author notes


    1. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Kunming, 650223, Yunnan, China

      • Cheng Xu
      • , Yunfei Wang
      • , Qiu Tu
      • , Zhiye Zhang
      • , James Mwangi
      • , Xudong Zhao
      •  & Ren Lai
    2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China

      • Cheng Xu
      • , Yunfei Wang
      •  & James Mwangi
    3. Life Sciences College of Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China

      • Mengrou Chen
      •  & Ren Lai
    4. Sino-African Joint Research Center, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, 650223, Yunnan, China

      • James Mwangi
      •  & Ren Lai
    5. Department of Cardiovascular Surgery, Yan’an Affiliated Hospital of Kunming Medical University, Kunming, 650041, Yunnan, China

      • Yaxiong Li
    6. Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway

      • Yang Jin


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