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.

中文翻译：

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靶向表面核仁蛋白通过AMPK激活诱导胰腺癌自噬依赖性细胞死亡。

尽管目前在包括外科手术和辅助疗法在内的常规疗法方面取得了进展，但胰腺癌仍然是最致命的人类癌症之一。在这里，我们显示LZ1，一种源自蛇毒cathelicidin的肽，通过在体外和体内诱导自噬依赖性细胞死亡，显着抑制了胰腺癌细胞的生长。LZ1诱导的细胞死亡被自噬的药理或遗传抑制所阻断。在胰腺癌的原位模型中，全身给药LZ1（1-4 mg / kg）与吉西他滨（20 mg / kg）相比显示出显着的抗肿瘤功效，显着延长了小鼠的存活率，并且不良反应可忽略不计。机理研究表明，LZ1通过与核仁素结合而起作用，而核仁素在胰腺癌细胞中的细胞表面表达经常增加。LZ1结合触发表面表达的核仁素的降解。这导致5'-AMP激酶激活，从而抑制mTORC1活性并诱导自噬通量。这些数据表明，靶向核仁素-AMPK-自噬轴的LZ1是开发针对胰腺癌的治疗剂的有希望的先导。