Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy.
1] Experimental Oncology Laboratories, Regina Elena National Cancer Institute, Rome, Italy [2] Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy.
Cell Death Dis. 2015 Jan 29;6(1):e1621. doi: 10.1038/cddis.2014.591.
Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation and survival. Several studies highlighted a critical role for MKK3 in tumor progression and invasion, and we previously identified MKK3 as transcriptional target of mutant (mut) p53 to sustain cell proliferation and survival, thus rendering MKK3 a promising target for anticancer therapies. Here, we found that targeting MKK3 with RNA interference, in both wild-type (wt) and mutp53-carrying cells, induced endoplasmic reticulum stress and autophagy that, respectively, contributed to stabilize wtp53 and degrade mutp53. MKK3 depletion reduced cancer cell proliferation and viability, whereas no significant effects were observed in normal cellular context. Noteworthy, MKK3 depletion in combination with chemotherapeutic agents increased tumor cell response to the drugs, in both wtp53 and mutp53 cancer cells, as demonstrated by enhanced poly (ADP-ribose) polymerase cleavage and reduced clonogenic ability in vitro. In addition, MKK3 depletion reduced tumor growth and improved biological response to chemotherapeutic in vivo. The overall results indicate MKK3 as a novel promising molecular target for the development of more efficient anticancer treatments in both wtp53- and mutp53-carrying tumors.
丝裂原活化蛋白激酶激酶 3（MAP2K3，MKK3）是双特异性蛋白激酶家族中的一员，属于 MAP 激酶激酶家族。这种激酶被有丝分裂原或应激诱导刺激激活，并参与 MAP 激酶介导的信号级联反应，导致细胞增殖和存活。几项研究强调了 MKK3 在肿瘤进展和侵袭中的关键作用，我们之前确定 MKK3 是突变型（mut）p53 的转录靶标，以维持细胞增殖和存活，因此 MKK3 是癌症治疗的有前途的靶点。在这里，我们发现用 RNA 干扰靶向 MKK3，无论是在野生型（wt）还是携带 mutp53 的细胞中，都会诱导内质网应激和自噬，这分别有助于稳定 wtp53 和降解 mutp53。MKK3 耗竭减少了癌细胞的增殖和活力，而在正常细胞环境中则没有观察到明显的影响。值得注意的是，MKK3 耗竭与化疗药物联合使用，增加了 wtp53 和 mutp53 癌细胞对药物的反应，如体外增强多聚（ADP-核糖）聚合酶切割和降低集落形成能力所示。此外，MKK3 耗竭减少了肿瘤生长，并改善了体内对化疗的生物学反应。总的来说，这些结果表明 MKK3 是一种新的有前途的分子靶点，可用于开发针对携带 wtp53 和 mutp53 的肿瘤的更有效的癌症治疗方法。
