Department of Surgery "P. Valdoni", "Sapienza" University of Rome, Rome, Italy.
J Pineal Res. 2014 Aug;57(1):120-9. doi: 10.1111/jpi.12150. Epub 2014 Jul 10.
Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over-expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome-dependent p53 degradation. MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K-AkT-dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2-dependent targeting of p53 is regulated in a nonlinear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated with reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down-regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt-PI3K-dependent MDM2 phosphorylation. Melatonin induces a 3-fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin-treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15-fold increase in p21 levels was observed in melatonin-treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect.
有强有力的证据表明，褪黑素可增加癌细胞中的 p53 活性。p53 乙酰化可使其稳定并激活，从而促进细胞凋亡/生长抑制。p300 的过表达可诱导 p53 乙酰化，通过增加 p21 的表达导致细胞生长停滞。反过来，p53 的激活主要通过 MDM2 在核内进行调节。MDM2 还作为 E3 泛素连接酶，通过促进蛋白酶体依赖性 p53 降解来促进细胞生长。MDM2 进入核内受到两种不同调节的精细调控：核糖体蛋白 L11 通过将 MDM2 隔离在细胞质中而起作用，而 PI3K-AkT 依赖性 MDM2 磷酸化对于 MDM2 跨核膜转运是必需的。此外，MDM2 依赖性 p53 靶向受 MDM2/MDMX 相互作用的非线性调节。褪黑素可抑制 MCF7 乳腺癌细胞的生长并诱导其凋亡。我们之前的研究表明，这种作用与 MDM2 水平降低和 p53 活性增加有关。在此，我们证明褪黑素可显著下调 MDM2 基因表达并抑制 MDM2 向核内转运，因为褪黑素可增加 L11 并抑制 Akt-PI3K 依赖性 MDM2 磷酸化。褪黑素可使 MDMX 和 p300 的水平分别增加 3 倍，同时降低 Sirt1（p300 活性的特异性抑制剂）。因此，褪黑素处理的细胞中 p53 和乙酰化 p53 的水平明显升高。因此，在褪黑素处理的癌细胞中观察到 p21 水平增加了 15 倍。我们的研究结果为褪黑素通过调节 MDM2/MDMX/p300 途径增强 p53 乙酰化提供了证据，为理解其抗癌作用提供了新的见解。
