p53 Activates the Lipoxygenase Activity of ALOX15B via Inhibiting SLC7A11 to Induce Ferroptosis in Bladder Cancer Cells

Abstract

Bladder cancer is a malignant tumor of the urinary system and is one of the most common cancers worldwide. Lipoxygenases are closely related to the development of various cancers. However, the relationship between lipoxygenases and p53/SLC7A11-dependent ferroptosis in bladder cancer has not been reported. Here, we aimed to investigate the roles and internal mechanisms of lipid peroxidation and p53/SLC7A11-dependent ferroptosis in the development and progression of bladder cancer. First, ultraperformance liquid chromatography-tandem mass spectrometry was performed to measure the metabolite production of lipid oxidation in patients' plasma. The metabolic changes in patients with bladder cancer were discovered, revealing that stevenin, melanin, and octyl butyrate were upregulated. Then, the expressions of lipoxygenase family members were measured to screen out candidates with significant changes in bladder cancer tissues. Among various lipoxygenases, ALOX15B was significantly downregulated in bladder cancer tissues. Moreover, p53 and 4-hydroxynonenal (4-HNE) levels were decreased in bladder cancer tissues. Next, sh-ALOX15B, oe-ALOX15B, or oe-SLC7A11 plasmids were constructed and transfected into bladder cancer cells. Then, the p53 agonist Nutlin-3a, tert-butyl hydroperoxide, iron chelator deferoxamine, and the selective ferroptosis inhibitor ferr1 were added. The effects of ALOX15B and p53/SLC7A11 on bladder cancer cells were evaluated by in vitro and in vivo experiments. We revealed that knockdown of ALOX15B promoted bladder cancer cell growth, which was also found to protect bladder cancer cells from p53-induced ferroptosis. Furthermore, p53 activated ALOX15B lipoxygenase activity by suppressing SLC7A11. Taken together, p53 activated the lipoxygenase activity of ALOX15B via inhibiting SLC7A11 to induce ferroptosis in bladder cancer cells, which provided insight into the molecular mechanism of the occurrence and development of bladder cancer.

Keywords: ALOX15B; bladder cancer; ferroptosis; metabolism; p53/SLC7A11.