Yoon Bada, Suresh Rajaghatta N, Shivakumara C S, Harsha Kachigere B, Mohan Chakrabhavi Dhananjaya, Sethi Gautam, Rangappa Kanchugarakoppal S, Ahn Kwang Seok
Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore, 570006, Karnataka, India.
Chem Biol Interact. 2025 Oct 22;420:111668. doi: 10.1016/j.cbi.2025.111668. Epub 2025 Jul 18.
Pancreatic cancer is characterized by aggressive progression, rapid metastasis, and resistance to conventional therapies, resulting in poor survival outcomes. Despite significant advances in research, effective treatment options for pancreatic cancer remain limited. In this study, we investigated the mechanisms of SRN-19-induced cell death in pancreatic cancer cells. Our findings demonstrated that SRN-19 promotes both apoptosis and paraptosis. Molecular analyses confirmed the upregulation of apoptotic markers, including cleaved PARP, Bax, and caspase-9/3, along with the downregulation of anti-apoptotic proteins Bcl-2 and Bcl-xL in both MIA PaCa-2 and AsPC-1 cells. Additionally, SRN-19 treatment led to reduced Alix expression and elevated levels of ATF4 and CHOP, markers associated with paraptosis, accompanied by alterations in mitochondrial membrane potential (MMP) in BxPC-3 cells. SRN-19 also induced a dose-dependent increase in reactive oxygen species (ROS) production and a corresponding decrease in the GSH/GSSG ratio. Pretreatment with N-acetylcysteine (NAC) attenuated ROS accumulation, restored Alix expression, and reduced cleaved PARP levels, confirming the involvement of ROS in apoptosis induction. Furthermore, SRN-19 activated the p38 MAPK pathway, and inhibition of p38 by SB203580 diminished ROS levels, reduced cleaved PARP expression, and restored MMP. Collectively, these results suggest that SRN-19 promotes ROS generation, activates the p38 MAPK pathway, and induces cell death in pancreatic cancer cells through both apoptotic and paraptotic mechanisms.
胰腺癌的特点是进展迅速、转移快且对传统疗法耐药，导致生存结果不佳。尽管研究取得了重大进展，但胰腺癌的有效治疗选择仍然有限。在本研究中，我们调查了SRN - 19诱导胰腺癌细胞死亡的机制。我们的研究结果表明，SRN - 19促进凋亡和类凋亡。分子分析证实，在MIA PaCa - 2和AsPC - 1细胞中，凋亡标志物（包括裂解的PARP、Bax和caspase - 9/3）上调，同时抗凋亡蛋白Bcl - 2和Bcl - xL下调。此外，SRN - 19处理导致Alix表达降低，与类凋亡相关的标志物ATF4和CHOP水平升高，同时BxPC - 3细胞中的线粒体膜电位（MMP）发生改变。SRN - 19还诱导活性氧（ROS）产生呈剂量依赖性增加，谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）比值相应降低。用N - 乙酰半胱氨酸（NAC）预处理可减轻ROS积累，恢复Alix表达，并降低裂解的PARP水平，证实ROS参与凋亡诱导。此外，SRN - 19激活p38丝裂原活化蛋白激酶（MAPK）途径，用SB203580抑制p38可降低ROS水平，减少裂解的PARP表达，并恢复MMP。总的来说，这些结果表明，SRN - 19促进ROS生成，激活p38 MAPK途径，并通过凋亡和类凋亡机制诱导胰腺癌细胞死亡。
