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

Oncogene volume 38, pages 1832–1844 (2019)Cite this article

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Abstract

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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Acknowledgements

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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    Authors and Affiliations

    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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    Xu, C., Wang, Y., Tu, Q. et al. Targeting surface nucleolin induces autophagy-dependent cell death in pancreatic cancer via AMPK activation. Oncogene 38, 1832–1844 (2019). https://doi.org/10.1038/s41388-018-0556-x

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