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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These authors contributed equally: Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang
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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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DOI: https://doi.org/10.1038/s41388-018-0556-x
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