Restelli Michela, Magni Martina, Ruscica Vincenzo, Pinciroli Patrizia, De Cecco Loris, Buscemi Giacomo, Delia Domenico, Zannini Laura
Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan 20133, Italy.
Department of Biochemistry, Max Planck Institute for Developmental Biology, Tubingen, Germany.
Cell Death Dis. 2016 Nov 3;7(11):e2453. doi: 10.1038/cddis.2016.359.
Human CCAR2 has recently emerged as having a pivotal role in the DNA damage response, promoting apoptosis and repair of heterochromatic DNA breaks. However, less is known about the function of CCAR2 in tumor formation and cancer progression. Here, we demonstrate, for the first time, that CCAR2 loss inhibits the proliferation of cancer cells, but preserves the growth of normal cells. Investigating the mechanisms responsible for this differential effect, we found that CCAR2 depletion specifically impairs the activation of AKT pathway in cancer cells, but not in normal cells, by reducing AKT phosphorylation on Ser473. This effect is achieved through the transcriptional upregulation of TRB3 gene and accumulation of TRB3 protein, which then binds to and inhibits the phosphorylation and activation of AKT. The defective activation of AKT finally results in reduced GSK3β phosphorylation, prevention of G1/S transition and inhibition of cancer cell growth. These results establish an important role for CCAR2 in cancer cells proliferation and could shed new light on novel therapeutic strategies against cancer, devoid of detrimental side effects.
人类CCAR2最近已成为在DNA损伤反应中起关键作用的因子，可促进异染色质DNA断裂的凋亡和修复。然而，关于CCAR2在肿瘤形成和癌症进展中的功能，人们了解较少。在此，我们首次证明，CCAR2缺失会抑制癌细胞增殖，但能维持正常细胞生长。在研究造成这种差异效应的机制时，我们发现，CCAR2缺失通过降低Ser473位点的AKT磷酸化水平，特异性损害癌细胞中AKT通路的激活，但对正常细胞无此影响。这种效应是通过TRB3基因的转录上调和TRB3蛋白的积累实现的，TRB3蛋白随后结合并抑制AKT的磷酸化和激活。AKT的缺陷激活最终导致GSK3β磷酸化水平降低，阻止G1/S期转换并抑制癌细胞生长。这些结果确立了CCAR2在癌细胞增殖中的重要作用，并可能为新型抗癌治疗策略提供新的思路，且无有害副作用。
