Kohli Jaskaren, Campisi Judith, Demaria Marco
European Research Institute for the Biology of Aging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Buck Institute for Research on Aging, Novato, CA, USA.
Oncotarget. 2017 Dec 28;9(7):7274-7281. doi: 10.18632/oncotarget.23752. eCollection 2018 Jan 26.
p16 is a potent cell cycle inhibitor engaged to support cell cycle arrest during cellular senescence. However, in tumors carrying mutations in key downstream effectors, p16 is highly expressed but fails to block cell proliferation. p16-overexpressing tumor cells are highly aggressive and no targeted interventions are available. To study the effect of specific therapies, we generated murine sarcomas by overexpressing RAS oncogene and disrupting p53 activity. We observed that p16-overxpressing murine sarcoma cells were resistant to ABT-263 and ABT-737, anti-cancer small molecules previously shown to eliminate p16 senescent cells. We then generated sarcoma cells carrying a suicide and reporter gene, called 3MR, under the regulation of the full p16 promoter. Activation of the suicide efficiently killed p16-overxpressing sarcoma cells and . These data suggest that suicide gene therapy could represent an important therapeutic approach for the treatment of highly aggressive p16 cancers.
p16是一种有效的细胞周期抑制剂，在细胞衰老过程中参与支持细胞周期停滞。然而，在关键下游效应器发生突变的肿瘤中，p16高度表达但未能阻止细胞增殖。过表达p16的肿瘤细胞具有高度侵袭性，且没有可用的靶向干预措施。为了研究特定疗法的效果，我们通过过表达RAS癌基因和破坏p53活性来生成小鼠肉瘤。我们观察到，过表达p16的小鼠肉瘤细胞对ABT - 263和ABT - 737具有抗性，这两种抗癌小分子先前已被证明可消除p16衰老细胞。然后，我们生成了在完整p16启动子调控下携带自杀和报告基因（称为3MR）的肉瘤细胞。自杀基因的激活有效地杀死了过表达p16的肉瘤细胞。这些数据表明，自杀基因疗法可能是治疗高度侵袭性p16癌症的一种重要治疗方法。
