Cao Ling-Zhi, Yang Fan-Hui, Zhang Hao, Jia Ai-Min, Li Su-Ping, Wen Hu-Ling
Department of Nuclear Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China.
Institute of Rheumatology and Immunology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China.
Discov Oncol. 2024 Jun 19;15(1):234. doi: 10.1007/s12672-024-01095-w.
Pancreatic cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression and immune evasion. Asperuloside (ASP) is an iridoid glycoside with potential anti-tumor properties. This study aimed to explore the molecular mechanisms of ASP on CAFs, particularly focusing on its effects on activating transcription factor 6 (ATF6), a key regulator of endoplasmic reticulum stress.
CAFs were treated with different concentrations of ASP (0, 1, 3, and 5 mM), and the role of ATF6 was investigated by over-expressing it in CAFs. Subsequently, western blot was used to detect ATF6, α-smooth muscle actin (α-SMA), fibroblast activating protein (FAP), and vimentin protein levels in CAFs. The collagen gel contraction assay and Transwell assay were applied to evaluate the contraction and migration ability of CAFs. In addition, the interleukin (IL)-6, C-C motif chemokine ligand (CCL)-2, and C-X-C motif chemokine ligand (CXCL)-10 levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).
CAFs had significantly higher expression levels of α-SMA, FAP, and vimentin compared to normal fibroblasts (NFs). ASP significantly inhibited the activation, contraction, and migration of CAFs in a concentration-dependent manner. ASP treatment also reduced the expression of cytokines (IL-6, CCL2, and CXCL10) and down-regulated ATF6 levels. Over-expression of ATF6 mitigated the inhibitory effects of ASP.
ASP exerts its anti-tumor effects by down-regulating ATF6, thereby inhibiting the activation and function of pancreatic CAFs. These findings suggest that ASP could be a promising therapeutic agent for pancreatic cancer by modulating the tumor microenvironment.
胰腺癌相关成纤维细胞（CAFs）在肿瘤进展和免疫逃逸中起关键作用。梓醇（ASP）是一种具有潜在抗肿瘤特性的环烯醚萜苷。本研究旨在探讨ASP对CAFs的分子作用机制，尤其关注其对激活转录因子6（ATF6）的影响，ATF6是内质网应激的关键调节因子。
用不同浓度的ASP（0、1、3和5 mM）处理CAFs，并通过在CAFs中过表达ATF6来研究其作用。随后，采用蛋白质免疫印迹法检测CAFs中ATF6、α平滑肌肌动蛋白（α-SMA）、成纤维细胞激活蛋白（FAP）和波形蛋白的蛋白水平。应用胶原凝胶收缩试验和Transwell试验评估CAFs的收缩和迁移能力。此外，通过逆转录-定量聚合酶链反应（RT-qPCR）检测白细胞介素（IL）-6、C-C基序趋化因子配体（CCL）-2和C-X-C基序趋化因子配体（CXCL）-10水平。
与正常成纤维细胞（NFs）相比，CAFs中α-SMA、FAP和波形蛋白的表达水平显著更高。ASP以浓度依赖性方式显著抑制CAFs的激活、收缩和迁移。ASP处理还降低了细胞因子（IL-6、CCL2和CXCL10）的表达并下调了ATF6水平。ATF6的过表达减轻了ASP的抑制作用。
ASP通过下调ATF6发挥其抗肿瘤作用，从而抑制胰腺CAFs的激活和功能。这些发现表明，ASP可能是一种通过调节肿瘤微环境治疗胰腺癌的有前景的治疗药物。
