Feng Tingting, Xu Xiaoying, Wang Xiao, Tang Wei, Lu Yi
Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Cell Death Dis. 2024 Dec 18;15(12):889. doi: 10.1038/s41419-024-07233-0.
Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.
颗粒蛋白前体（PGRN）是一种在多种肿瘤中具有致瘤作用的自分泌生长因子，在体外是正常细胞和癌细胞的一种假定存活因子。然而，PGRN介导的癌细胞在遭受各种类型的微环境应激（如血清剥夺）时存活的基本机制仍不清楚。我们在此表明，血清剥夺会降低宫颈癌细胞内的PGRN蛋白水平。PGRN可保护宫颈癌细胞免受血清剥夺诱导的凋亡，限制活性氧（ROS）水平，维持线粒体完整性，并减少蛋白质、脂质和DNA的氧化损伤。PGRN增强了ROS清除系统，血清撤除后宫颈癌细胞中超氧化物歧化酶（SOD）、过氧化氢酶蛋白表达和活性增加、谷胱甘肽（GSH）和烟酰胺腺嘌呤二核苷酸磷酸（NADPH）水平升高以及II期解毒酶表达增加均证明了这一点。PGRN在ROS清除中的作用是由PGRN刺激的核因子红细胞衍生2样2（NFE2L2）-抗氧化反应元件（ARE）途径介导的。我们的研究揭示了PGRN在支持氧化应激下宫颈癌细胞存活中的抗氧化作用。这一见解为宫颈癌细胞如何适应微环境应激提供了新的视角，有助于细胞活力和其他恶性特征。
