We have previously reported that Monoglyceride Lipase (MGL) expression is absent or reduced in various human malignancies and MGL-deficient mice develop tumors in multiple organs. Evidence also suggests MGL to be a tumor suppressor, however, the mechanisms underlying its tumor-suppressive actions remain to be investigated. Here, we report a novel function of MGL as a negative regulator of XIAP, an important inhibitor of apoptosis. We found that MGL directly interacted with XIAP and enhanced E3-ligase activity and proteasomal degradation of XIAP. MGL overexpression induced cell death that was coupled with caspase activation and reduced XIAP levels. N-terminus of MGL was found to mediate interactions with XIAP and induce cell death. MGL-deficient cells exhibited elevated XIAP levels and exhibited resistance to anticancer drugs. XIAP expression was significantly elevated in tissues of MGL-deficient animals as well as human lung cancers exhibiting reduced MGL expression. Thus, MGL appears to mediate its tumor-suppressive actions by inhibiting XIAP to induce cell death.

中文翻译：

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单甘酯脂肪酶通过促进 X 连锁凋亡蛋白抑制剂的降解来介导肿瘤抑制作用。

我们以前曾报道过，单甘酯脂肪酶 (MGL) 表达在各种人类恶性肿瘤中不存在或减少，MGL 缺陷小鼠在多个器官中形成肿瘤。证据还表明 MGL 是一种肿瘤抑制因子，然而，其肿瘤抑制作用的机制仍有待研究。在这里，我们报告了 MGL 作为 XIAP 的负调节因子的新功能，XIAP 是一种重要的细胞凋亡抑制剂。我们发现 MGL 直接与 XIAP 相互作用并增强了 XIAP 的 E3-连接酶活性和蛋白酶体降解。MGL 过表达诱导细胞死亡，这与半胱天冬酶激活和降低的 XIAP 水平相结合。发现 MGL 的 N 端介导与 XIAP 的相互作用并诱导细胞死亡。MGL 缺陷细胞表现出升高的 XIAP 水平并对抗癌药物表现出抗性。XIAP 表达在 MGL 缺陷动物以及 MGL 表达降低的人类肺癌组织中显着升高。因此，MGL 似乎通过抑制 XIAP 诱导细胞死亡来介导其肿瘤抑制作用。