Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer

作者：Özge Saatci, Rashedul Alam, Kim‐Tuyen Huynh‐Dam, Aynur Işık, Meral Üner, Nevin Belder, Pelin G. Ersan, Ünal Metin Tokat, Bürge Ulukan, Metin Çetįn, Kübra Çalışır, Mustafa Emre Gedik, Hilal Bal, Ozlem Sener Sahin, Ozlem Sener Sahin, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Öğretmen, Sercan Aksoy, Ayşegül Üner, Aytekin Akyol, Özgür Şahin, Özgür Şahin · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-06814-3 · 被引用次数：32 · 研究领域：Cancer-related molecular mechanisms research、RNA Research and Splicing、Ferroptosis and cancer prognosis

Abstract Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D ( PDE4D ), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca 2+ channel. This causes cytosolic Ca 2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe 2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca 2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca 2+ /ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-tr...