p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.
p53-inducible SESTRINs might play opposite roles in the regulation of early and late stages of lung carcinogenesis.
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DOI：
10.18632/oncotarget.27367
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发表时间：
2019-12-10
期刊：
影响因子：
--
通讯作者：
Budanov, Andrei V
中科院分区：
文献类型：
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作者：
Ding, Boxiao;Haidurov, Alexander;Budanov, Andrei V
SESTRIN (SESN1-3) 是由进化上保守的基因家族编码的蛋白质，在调节细胞活力和代谢以应对压力方面发挥着重要作用。 SESTRIN 的许多作用是通过分别对雷帕霉素激酶复合物 1 和 2（mTORC1 和 mTORC2）的机械靶标的负调节和正调节来介导的，这些靶标在人类癌症中经常失调，支持细胞生长、增殖和细胞活力。除了调节 mTORC1/2 之外，SESTRIN 还可以控制活性氧的积累、细胞死亡和线粒体自噬。 SESN1 和 SESN2 是肿瘤抑制蛋白 p53 的转录靶标，可能介导 p53 的肿瘤抑制活性。因此，我们基于小鼠肺癌模型和人肺腺癌A549细胞进行研究，以评估SESN1和SESN2对肺癌发生的潜在影响。虽然我们观察到人类肿瘤中 SESN1 和 SESN2 的表达通常会降低，但小鼠中 Sesn2 的失活通过与 AKT 激活相关的机制正向调节肿瘤生长，而 Sesn1 的敲除对 Sesn2 缺陷小鼠的致癌作用没有额外影响。然而，A549 细胞中 SESN1 和/或 SESN2 的失活会加速细胞增殖，并抵抗葡萄糖饥饿引起的细胞死亡。我们认为，尽管 SESTRIN 对早期肿瘤生长有贡献，但 SESTRIN 可能在营养缺乏的情况下通过抑制细胞增殖或激活细胞死亡来抑制晚期癌症发生。
SESTRINs (SESN1-3) are proteins encoded by an evolutionarily conserved gene family that plays an important role in the regulation of cell viability and metabolism in response to stress. Many of the effects of SESTRINs are mediated by negative and positive regulation of mechanistic target of rapamycin kinase complexes 1 and 2 (mTORC1 and mTORC2), respectively, that are often deregulated in human cancers where they support cell growth, proliferation, and cell viability. Besides their effects on regulation of mTORC1/2, SESTRINs also control the accumulation of reactive oxygen species, cell death, and mitophagy. SESN1 and SESN2 are transcriptional targets of tumor suppressor protein p53 and may mediate tumor suppressor activities of p53. Therefore, we conducted studies based on a mouse lung cancer model and human lung adenocarcinoma A549 cells to evaluate the potential impact of SESN1 and SESN2 on lung carcinogenesis. While we observed that expression of SESN1 and SESN2 is often decreased in human tumors, inactivation of Sesn2 in mice positively regulates tumor growth through a mechanism associated with activation of AKT, while knockout of Sesn1 has no additional impact on carcinogenesis in Sesn2-deficient mice. However, inactivation of SESN1 and/or SESN2 in A549 cells accelerates cell proliferation and imparts resistance to cell death in response to glucose starvation. We propose that despite their contribution to early tumor growth, SESTRINs might suppress late stages of carcinogenesis through inhibition of cell proliferation or activation of cell death in conditions of nutrient deficiency.