ABSTRACT

Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter “autophagy”) is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer.

Abbreviations: AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.

摘要

KRAS 致癌突变驱动的胰腺导管腺癌目前是美国癌症相关死亡的第四大原因。巨自噬（以下简称“自噬”）是溶酶体依赖性降解系统之一，可以通过激活动态膜结构（例如吞噬团、自噬体和自溶酶体）去除异常蛋白质、受损细胞器或入侵病原体。自噬受损（包括过度激活和缺陷）是包括胰腺癌在内的人类疾病的病理特征。然而，功能失调的自噬有多种类型，并在胰腺肿瘤生物学中发挥着复杂的作用，具体取决于肿瘤分期、微环境、免疫代谢状态和死亡信号等多种因素。作为连接各种细胞事件的调节剂，非选择性自噬的药理学靶向可能会导致好的和坏的治疗效果。相反，针对选择性自噬可以减少所用药物的潜在副作用。在这篇综述中，我们描述了自噬在胰腺癌的发展和治疗中的进展和挑战。

缩写：AMPK：AMP 激活蛋白激酶；CQ：氯喹；csc：癌症干细胞；DAMP：危险/损害相关的分子模式；EMT：上皮间质转化；lncRNA：长非编码RNA；MIR：微小RNA；PanIN：胰腺上皮内瘤变；PDAC：胰腺导管腺癌；PtdIns3K: 磷脂酰肌醇 3-激酶；SNARE：可溶性NSF附着蛋白受体；UPS：泛素-蛋白酶体系统。