Romeo Maria Anele, Gilardini Montani Maria Saveria, Arena Andrea, Benedetti Rossella, D'Orazi Gabriella, Cirone Mara
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00128 Rome, Italy.
Biomedicines. 2022 Oct 5;10(10):2489. doi: 10.3390/biomedicines10102489.
It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells. At the molecular level, we observed that c-Myc inhibition reduced the expression of mevalonate kinase (MVK), a molecule belonging to the mevalonate pathway that-according to previous findings-can control mutp53 stability, and thus contributes to cancer cell survival. In conclusion, this study unveils another criminal alliance between oncogenes, such as c-Myc and mutp53, that plays a key role in oncogenesis.
已有研究表明，野生型（wt）p53可抑制癌基因c-Myc，而突变型（mut）p53可能会反式激活它，这种相反的行为在wt或mutp53与促进癌变的分子/信号通路的相互作用中经常出现。即使已有报道称mutp53可维持c-Myc的表达，但c-Myc是否反过来影响mutp53的表达仍有待研究。在本研究中，我们发现对c-Myc进行药理学或遗传学抑制可下调mutp53，损害胰腺癌细胞的存活并增加DNA损伤。在分子水平上，我们观察到c-Myc抑制可降低甲羟戊酸激酶（MVK）的表达，MVK是甲羟戊酸途径中的一个分子，根据先前的研究结果，它可以控制mutp53的稳定性，从而有助于癌细胞的存活。总之，本研究揭示了癌基因如c-Myc和mutp53之间的另一个罪恶联盟，它们在肿瘤发生中起关键作用。
