Verteporfin induces lipid peroxidation and ferroptosis in pancreatic cancer cells. Free Radic Biol Med 2024 Feb 20;212:493-504
Date
01/07/2024Pubmed ID
38184120Pubmed Central ID
PMC10906657DOI
10.1016/j.freeradbiomed.2024.01.003Scopus ID
2-s2.0-85182384342 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP inhibitor. The efficacy of VP on human cancer are being tested in several trials. In this study, we examined the effect of VP on reactive oxygen species (ROS) and lipid peroxidation in pancreatic cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of light activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of glutathione peroxidase 4 (GPX4), an enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and ferroptosis in the absence of light activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic cancer.
Author List
Zhou W, Lim A, Elmadbouh OHM, Edderkaoui M, Osipov A, Mathison AJ, Urrutia R, Liu T, Wang Q, Pandol SJAuthors
Angela Mathison PhD Assistant Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Carcinoma, Pancreatic DuctalHumans
Lipid Peroxidation
Pancreatic Neoplasms
Reactive Oxygen Species
