Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer
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, Yasser Riazalhosseini, Denis Thieffry, Daniel Gautheret, Besim Öğretmen, Sercan Aksoy, Ayşegül Üner, Aytekin Akyol, Özgür Şahin, Özgür Şahin, Özgür Şahin
Abstract
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-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca 2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.