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

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.

• Authors: Cheng Xu, Yunfei Wang, Qiu Tu, Zhiye Zhang, Mengrou Chen, James Mwangi, Yaxiong Li, Yang Jin, Xudong Zhao, Ren Lai
• Journal: Oncogene (Oncogene) Vol. 38 Issue 11 Pg. 1832-1844 (03 2019) ISSN: 1476-5594 [Electronic] England
• PMID: 30356139 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Surface
• Antineoplastic Agents
• Peptide Fragments
• Phosphoproteins
• RNA-Binding Proteins
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Animals
• Antigens, Surface (drug effects, metabolism)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Autophagy (drug effects)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism, pathology)
• Cell Death (drug effects)
• Cells, Cultured
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Targeted Therapy (methods)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Peptide Fragments (pharmacology, therapeutic use)
• Phosphoproteins (antagonists & inhibitors)
• RNA-Binding Proteins (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays
• Nucleolin