Novel SERCA2 inhibitor Diphyllin displays anti-tumor effect in non-small cell lung cancer by promoting endoplasmic reticulum stress and mitochondrial dysfunction

• Published in: Cancer letters 2024-08, Vol.598, p.217075, Article 217075
• Main Authors: Xu, Zhiyong, Shi, Yueli, Zhu, Liang, Luo, Jianhua, Hu, Qiongjie, Jiang, Sujing, Xiao, Mingshu, Jiang, Xinyuan, Wang, Huan, Xu, Yun, Jin, Wei, Zhou, Yan, Wang, Pingli, Wang, Kai
• Format: Article
• Language: English
• Subjects: Calcium signaling; ER stress; Mitochondrial dysfunction; Non-small cell lung cancer; ROS
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2024.217075

Abnormal calcium signaling is associated with non-small cell lung cancer (NSCLC) malignant progression, poor survival and chemotherapy resistance. Targeting endoplasmic reticulum (ER) Ca2+ channels or pumps to block calcium uptake in the ER induces ER stress and concomitantly promotes mitochondrial calcium uptake, leading to mitochondrial dysfunction and ultimately inducing cell death. Here, we identified Diphyllin was a potential specific inhibitor of endoplasmic reticulum (ER) calcium-importing protein sarco/endoplasmic-reticulum Ca2+ ATPase 2 (SERCA2). In vitro and in vivo studies showed that Diphyllin increased NSCLC cell apoptosis, along with inhibition of cell proliferation and migration. Mechanistically, Diphyllin promoted ER stress by directly inhibiting SERCA2 activity and decreasing ER Ca2+ levels. At the same time, the accumulated Ca2+ in cytoplasm flowed into mitochondria to increase reactive oxygen species (ROS) and decrease mitochondrial membrane potential (MMP), leading to cytochrome C (Cyto C) release and mitochondrial dysfunction. In addition, we found that Diphyllin combined with cisplatin could have a synergistic anti-tumor effect in vitro and in vivo. Taken together, our results suggested that Diphyllin, as a potential novel inhibitor of SERCA2, exerts anti-tumor effects by blocking ER Ca2+ uptake and thereby promoting ER stress and mitochondrial dysfunction. •Diphyllin induces apoptosis via blocking Ca2+ uptake in the ER and promoting mitochondrial Ca2+ accumulation.•Abnormal Ca2+ distribution induced by Diphyllin contributes to ER stress and mitochondrial dysfunction.•Diphyllin decreases ER Ca2+ levels by targeting SERCA2 and inhibiting its activity.•Diphyllin inhibits tumor growth and metastasis in vivo.