Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Lab Invest. 2023 May;103(5):100058. doi: 10.1016/j.labinv.2022.100058. Epub 2023 Jan 10.
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.
膀胱癌是泌尿系统的一种恶性肿瘤，是全球最常见的癌症之一。脂氧合酶与各种癌症的发展密切相关。然而，脂氧合酶与 p53/SLC7A11 依赖性铁死亡在膀胱癌中的关系尚未报道。在这里，我们旨在研究脂质过氧化和 p53/SLC7A11 依赖性铁死亡在膀胱癌发生和发展中的作用和内在机制。首先，采用超高效液相色谱-串联质谱法测定患者血浆中脂质氧化产物的代谢产物。发现膀胱癌患者的代谢变化，揭示 Stevenin、黑色素和辛酸丁酯上调。然后，测量脂氧合酶家族成员的表达，以筛选出膀胱癌组织中变化显著的候选物。在各种脂氧合酶中，ALOX15B 在膀胱癌组织中显著下调。此外，膀胱癌组织中 p53 和 4-羟基壬烯醛（4-HNE）水平降低。接下来，构建 sh-ALOX15B、oe-ALOX15B 或 oe-SLC7A11 质粒并转染膀胱癌细胞。然后加入 p53 激动剂 Nutlin-3a、叔丁基过氧化氢、铁螯合剂去铁胺和选择性铁死亡抑制剂 ferr1。通过体外和体内实验评估 ALOX15B 和 p53/SLC7A11 对膀胱癌细胞的影响。我们揭示了敲低 ALOX15B 促进了膀胱癌细胞的生长，这也发现了它可以保护膀胱癌细胞免受 p53 诱导的铁死亡。此外，p53 通过抑制 SLC7A11 激活 ALOX15B 脂氧合酶活性。总之，p53 通过抑制 SLC7A11 激活 ALOX15B 脂氧合酶活性，诱导膀胱癌细胞发生铁死亡，为膀胱癌的发生和发展提供了分子机制的见解。
