Li Na, Zhang Xiaozhe, Chen Jingyi, Gao Shan, Wang Lei, Zhao Yanxiang
Shenzhen Research Institute, The Hong Kong Polytechnic University, Shenzhen 518057, China.
State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong 999077, China.
Cancers (Basel). 2023 Feb 2;15(3):953. doi: 10.3390/cancers15030953.
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, with a dismal five-year survival rate of less than 10%. PDAC possesses prominent genetic alterations in the oncogene KRAS and tumor suppressors p53, SMAD4 and CDKN2A. However, efforts to develop targeted drugs against these molecules have not been successful, and novel therapeutic modalities for PDAC treatment are urgently needed. Autophagy is an evolutionarily conserved self-degradative process that turns over intracellular components in a lysosome-dependent manner. The role of autophagy in PDAC is complicated and context-dependent. Elevated basal autophagy activity has been detected in multiple human PDAC cell lines and primary tumors resected from patients. However, clinical trials using chloroquine (CQ) to inhibit autophagy failed to show therapeutic efficacy. Here we show that a Beclin 1-targeting stapled peptide (Tat-SP4) developed in our lab further enhanced autophagy in multiple PDAC cell lines possessing high basal autophagy activity. Tat-SP4 also triggered faster endolysosomal degradation of EGFR and induced significant mitochondria stress as evidenced by partial loss of Δψ, increased level of ROS and reduced OXPHOS activity. Tat-SP4 exerted a potent anti-proliferative effect in PDAC cell lines in vitro and prohibited xenograft tumor growth in vivo. Intriguingly, excessive autophagy has been reported to trigger a unique form of cell death termed autosis. Tat-SP4 does induce autosis-like features in PDAC cells, including mitochondria stress and non-apoptotic cell death. Overall, our study suggests that autophagy perturbation by a Beclin 1-targeting peptide and the resulting autosis may offer a new strategy for PDAC drug discovery.
胰腺导管腺癌（PDAC）是最常见的胰腺癌类型，其五年生存率低至不到10%，令人沮丧。PDAC在癌基因KRAS以及肿瘤抑制因子p53、SMAD4和CDKN2A中存在显著的基因改变。然而，开发针对这些分子的靶向药物的努力尚未成功，因此迫切需要用于PDAC治疗的新型治疗方法。自噬是一种进化上保守的自我降解过程，它以溶酶体依赖的方式更新细胞内成分。自噬在PDAC中的作用复杂且依赖于具体情况。在多种人类PDAC细胞系和从患者切除的原发性肿瘤中均检测到基础自噬活性升高。然而，使用氯喹（CQ）抑制自噬的临床试验未能显示出治疗效果。在此我们表明，我们实验室开发的一种靶向Beclin 1的订书肽（Tat-SP4）在多个具有高基础自噬活性的PDAC细胞系中进一步增强了自噬。Tat-SP4还引发了表皮生长因子受体（EGFR）更快的内溶酶体降解，并诱导了显著的线粒体应激，这表现为线粒体膜电位（Δψ）部分丧失、活性氧（ROS）水平升高以及氧化磷酸化（OXPHOS）活性降低。Tat-SP4在体外对PDAC细胞系发挥了强大的抗增殖作用，并在体内抑制了异种移植肿瘤的生长。有趣的是，据报道过度自噬会引发一种独特的细胞死亡形式，称为自噬性细胞死亡。Tat-SP4确实在PDAC细胞中诱导了类似自噬性细胞死亡的特征，包括线粒体应激和非凋亡性细胞死亡。总体而言，我们的研究表明，通过靶向Beclin 1的肽干扰自噬以及由此产生的自噬性细胞死亡可能为PDAC药物研发提供一种新策略。
